WO2002066422A1 - Phenethanolamine derivatives for treatment of respiratory diseases - Google Patents

Phenethanolamine derivatives for treatment of respiratory diseases Download PDF

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Publication number
WO2002066422A1
WO2002066422A1 PCT/EP2002/001387 EP0201387W WO02066422A1 WO 2002066422 A1 WO2002066422 A1 WO 2002066422A1 EP 0201387 W EP0201387 W EP 0201387W WO 02066422 A1 WO02066422 A1 WO 02066422A1
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WO
WIPO (PCT)
Prior art keywords
oxy
formula
hexyl
phenyl
benzodioxin
Prior art date
Application number
PCT/EP2002/001387
Other languages
French (fr)
Inventor
Keith Biggadike
Diane Mary Coe
Dean David Edney
Abigail Halton
Brian Edgar Looker
Michael John Monteith
Rebecca Jane Moore
Rajnikant Patel
Panayiotis Alexandrou Procopiou
Stephen Barry Guntrip
Original Assignee
Glaxo Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to GBGB0103630.0A priority Critical patent/GB0103630D0/en
Priority claimed from GB0126998A external-priority patent/GB0126998D0/en
Priority to EP02706735A priority patent/EP1360174A1/en
Priority to JP2002565940A priority patent/JP4029042B2/en
Priority to NZ527404A priority patent/NZ527404A/en
Priority to CA002437977A priority patent/CA2437977A1/en
Priority to MXPA03007262A priority patent/MXPA03007262A/en
Priority to BR0207694-2A priority patent/BR0207694A/en
Priority to DZ023500A priority patent/DZ3500A1/en
Priority to IL15714902A priority patent/IL157149A0/en
Priority to KR1020037010667A priority patent/KR100880763B1/en
Priority to SK1021-2003A priority patent/SK10212003A3/en
Priority to HU0400699A priority patent/HUP0400699A2/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to EA200300776A priority patent/EA006646B1/en
Priority to APAP/P/2003/002842A priority patent/AP2088A/en
Priority to US10/467,733 priority patent/US7135600B2/en
Priority to AU2002240924A priority patent/AU2002240924B2/en
Publication of WO2002066422A1 publication Critical patent/WO2002066422A1/en
Priority to UA2003087450A priority patent/UA76443C2/en
Priority to ZA200306234A priority patent/ZA200306234B/en
Priority to NO20033594A priority patent/NO20033594L/en
Priority to EC2003004732A priority patent/ECSP034732A/en
Priority to US11/207,967 priority patent/US7442719B2/en
Priority to US11/426,661 priority patent/US7442837B2/en
Priority to US11/426,657 priority patent/US7442836B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/23—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
    • C07C311/27—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/52—Y being a hetero atom
    • C07C311/54—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea
    • C07C311/57—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/58—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings having nitrogen atoms of the sulfonylurea groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention is concerned with phenethanolamine derivatives, processes for their preparation, compositions containing them and their use in medicine, particularly in the prophylaxis and treatment of respiratory diseases.
  • phenethanolamine compounds are known in the art as having selective stimulant action at ⁇ 2 -adrenoreceptors and therefore having utility in the treatment of bronchial asthma and related disorders.
  • GB 2 140 800 describes phenethanolamine compounds including 4- hydroxy- ⁇ '-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-l,3-benzenedimethanol l-hydroxy-2- naphthalenecarboxylate (salmeterol xinafoate) which is now used clinically in the treatment of such medical conditions.
  • n is an integer of from 3 to 1 1 , preferably from 3 to 7; with the proviso that m + n is 5 to 19, preferably 5 to 12;
  • R 1 is -XS0 2 NR 6 R 7
  • X is -(CH ) P - or C 2 -e alkenylene
  • R 6 and R 7 are independently selected from hydrogen, C 3 . 7 cycloalkyl, C(O)NR 8 R 9 , phenyl, and phenyl (C ⁇ alkyl)-, or R 6 and R 7 , together with the nitrogen to which they are bonded, form a 5-, 6-, or 7- membered nitrogen containing ring, and R 6 and R 7 are each optionally substituted by one or two groups selected from halo, C,. 6 alkyl, C,. 6 haloalkyl, C,. 6 alkoxy, hydroxy-substituted C,.
  • R 8 and R 9 are independently selected from hydrogen, C ⁇ _ 6 alkyl, C 3 . 6 cycloalkyl, phenyl, and phenyl (C alkyl)-; and p is an integer of from 0 to 6, preferably from 0 to 4;
  • R 2 and R 3 are independently selected from hydrogen, halo, phenyl, and C
  • R 4 and R 5 are independently selected from hydrogen and C]. alkyl with the proviso that the total number of carbon atoms in R 4 and R 5 is not more than 4.
  • the group R 1 is preferably attached to the meta-position relative to the -0-(CH 2 ) n - link.
  • R 1 preferably represents -S0 2 NR 6 R 7 wherein R 6 and R 7 are independently selected from hydrogen and more preferably R 1 is -SO 2 NH 2 .
  • R 4 and R 5 are preferably independently selected from hydrogen and methyl, more preferably R 4 and R 5 are both hydrogen.
  • n is suitably 4, 5, or 6, and n is suitably 3, 4, 5 or 6.
  • m is 5 or 6 and n is 3 or 4, such that m + n is 8, 9 or 10, preferably 9.
  • R 1 is as defined above for formula (I).
  • R 1 is as defined above for formula (I).
  • the group R 1 is preferably attached to the rneta- position relative to the -0-(CH 2 ) n -, -O-(CH 2 ) - or -0-(CH 2 ) 3 - link respectively.
  • R 1 is preferably -S0 2 NR 6 R 7 wherein R 6 and R 7 are independently selected from hydrogen and more preferably R 1 is -SO 2 NH 2 .
  • Preferred compounds of the invention include:
  • Particularly preferred compounds of the invention include:
  • R 1 where 'R 6 and R 7 together with the nitrogen atom to which they are bonded, form a 5-, 6-, or 7- membered nitrogen containing ring'
  • the term "5-, 6-, or 7- membered nitrogen containing ring” means a 5-, 6-, or 7- membered saturated or unsaturated ring which includes the sulfonamide nitrogen atom and optionally 1 or 2 other heteroatoms independently selected from nitrogen, sulphur, and oxygen.
  • Suitable examples of such a ring include piperidinyl, morpholinyl, and piperazinyl.
  • the term "5-, 6-, or 7- membered heterocyclic ring” means a 5-, 6-, or 7- membered fully or partially saturated or unsaturated ring which includes 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, sulphur, and oxygen.
  • Suitable examples of such a ring include pyrrolyl, furyl, thienyl, pyridinyl, pyrazinyl, pyridazinyl, imidazolyl, tetrazolyl, tetrahydrofuranyl, oxazolyl, thiazolyl, thiadiazolyl, piperidinyl, morpholinyl, and piperazinyl.
  • the compounds of formulae (I), (la) and (lb) include an asymmetric centre, namely the carbon atom of the
  • the present invention includes both (S) and (R) enantiomers either in substantially pure form or admixed in any proportions.
  • R 4 and R 5 are different groups
  • the carbon atom to which they are attached is an asymmetric centre and the present invention includes both (S) and (R) enantiomers at this centre either in substantially pure form or admixed in any proportions.
  • Salts and solvates of compounds of formulae (I), (la) and (lb) which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable.
  • salts and solvates having non-pharmaceutical ly acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formulae (I), (la) and (lb) and their pharmaceutically acceptable salts, solvates, and physiologically functional derivatives.
  • physiologically functional derivative is meant a chemical derivative of a compound of formula (I), (la) or (lb) having the same physiological function as the parent compound of formula (I), (la) or (lb), for example, by being convertible in the body thereto.
  • physiologically functional derivatives include esters.
  • Suitable salts according to the invention include those formed with both organic and inorganic acids or bases.
  • Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, triphenyl acetic, sulphamic, sulphanilic, succinic, oxalic, fumaric, maleic, malic, glutamic, aspartic, oxaloacetic, methanesulphonic, ethanesulphonic, arylsulphonic (for example p-toluenesulphonic, benzenesulphonic, naphthalenesulphonic or naphthalenedisulphonic), salicylic, glutaric, gluconic, tricarballylic, cinnamic, substituted cinnamic (for example, phenyl, methyl , methoxy or halo substitute
  • Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases such as dicyclohexyl amine and N-methyl-D-glucamine.
  • preferred compounds of the invention such as 3-(4- ⁇ [6-( ⁇ (2R)-2-hydroxy-2-[4- hydroxy-3-(hydroxymethyl)-phenyl]ethyl ⁇ amino)hexyl]oxy ⁇ butyl)benzenesulfonamide and 3- (3 - ⁇ [7-( ⁇ (2R)-2-hydroxy-2- [4-hydroxy-3 -hydroxymethyl)phenyl]ethyl ⁇ - amino)heptyl]oxy ⁇ propyl)benzenesulfonamide are provided in the form of a crystalline salt, for example selected from those exemplified in the experimental section below. Said crystalline salts have favourable physical properties such as low hygroscopicity and/or improved stability.
  • Particularly preferred salts include the cinnamate, 4-methoxycinnamate, 4-methylcinnamate, naphthalenepropenoate and 4-phenylcinnamate salts.
  • esters of the compounds of formulae (I), (la) and (lb) may have a hydroxyl group converted to a C ⁇ alkyl, aryl, aryl C ⁇ . 6 alkyl, or amino acid ester.
  • the compounds of formulae (I), (la) and (lb) are selective ⁇ 2 - adrenoreceptor agonists as demonstrated using functional or reporter gene readout from cell lines transfected with human beta-adrenoreceptors as described below.
  • Compounds according to the present invention also have the potential to combine long duration of effect with rapid onset of action.
  • certain compounds have shown an improved therapeutic index in animal models relative to existing long-acting ⁇ 2 -agonist bronchodilators. As such, compounds of the invention may be suitable for once-daily administration.
  • Compounds of formulae (I), (la) and (lb) and their pharmaceutically acceptable salts, solvates, and physiologically functional derivatives have use in the prophylaxis and treatment of clinical conditions for which a selective ⁇ 2 -adrenoreceptor agonist is indicated.
  • Such conditions include diseases associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary diseases (COPD) (e.g. chronic and whez bronchitis, emphysema), respiratory tract infection and upper respiratory tract disease (e.g. rhinitis, including seasonal and allergic rhinitis).
  • COPD chronic obstructive pulmonary diseases
  • rhinitis e.g. chronic and whez bronchitis, emphysema
  • respiratory tract infection e.g. rhinitis, including seasonal and allergic rhinitis.
  • Other conditions which may be treated include premature labour, depression, congestive heart failure, skin diseases (e.g. inflammatory, allergic, psoriatic, and proliferative skin diseases), conditions where lowering peptic acidity is desirable (e.g. peptic and gastric ulceration) and muscle wasting disease.
  • skin diseases e.g. inflammatory, allergic, psoriatic, and proliferative skin diseases
  • conditions where lowering peptic acidity is desirable e.g. peptic and gastric ulceration
  • muscle wasting disease e.g. peptic and gastric ulceration
  • the present invention provides a method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which a selective ⁇ 2 -adrenoreceptor agonist is indicated, which comprises administration of a therapeutically effective amount of a compound of formula (I), (la) or (lb), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
  • a mammal such as a human
  • a selective ⁇ 2 -adrenoreceptor agonist is indicated
  • the present invention provides such a method for the prophylaxis or treatment of a disease associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease.
  • COPD chronic obstructive pulmonary disease
  • the present invention provides such a method for the prophylaxis or treatment of a clinical condition selected from premature labour, depression, congestive heart failure, skin diseases (e.g. inflammatory, allergic, psoriatic, and proliferative skin diseases), conditions where lowering peptic acidity is desirable (e.g. peptic and gastric ulceration) or muscle wasting disease.
  • a clinical condition selected from premature labour, depression, congestive heart failure, skin diseases (e.g. inflammatory, allergic, psoriatic, and proliferative skin diseases), conditions where lowering peptic acidity is desirable (e.g. peptic and gastric ulceration) or muscle wasting disease.
  • a compound of formula (I), (la) or (lb) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for use in medical therapy, particularly, for use in the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which a selective ⁇ 2 -adrenoreceptor agonist is indicated.
  • a compound of formula (I), (la) or (lb) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for the prophylaxis or treatment of a disease associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease.
  • COPD chronic obstructive pulmonary disease
  • a clinical condition selected from premature labour, depression, congestive heart failure, skin diseases (e.g. inflammatory, allergic, psoriatic, and proliferative skin diseases), conditions where lowering peptic acidity is desirable (e.g. peptic and gastric ulceration) or muscle wasting disease.
  • the present invention also provides the use of a compound of formula (I), (la) or (lb), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which a selective ⁇ 2 -adrenoreceptor agonist is indicated, for example a disease associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease.
  • COPD chronic obstructive pulmonary disease
  • a clinical condition selected from premature labour, depression, congestive heart failure, skin diseases (e.g. inflammatory, allergic, psoriatic, and proliferative skin diseases), conditions where lowering peptic acidity is desirable (e.g. peptic and gastric ulceration) and muscle wasting disease.
  • the amount of a compound of formula (I), (la) or (lb), or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, and the particular disorder or disease being treated.
  • the compounds of the invention may be administered by inhalation at a dose of from 0.0005mg to 10 mg, preferably 0.005mg to 0.5mg.
  • the dose range for adult humans is generally from 0.0005 mg to lOOmg per day and preferably 0.01 mg to lmg per day.
  • the present invention further provides a pharmaceutical formulation comprising a compound of formula (I), (la) or (lb) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients.
  • active ingredient means a compound of formula (I), (la) or (lb), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), inhalation (including fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulisers or insufflators), rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-injection, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine, or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator.
  • Formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier substance) such as lactose or starch. Use of lactose is preferred.
  • Carrier substance such as lactose or starch.
  • lactose lactose or starch.
  • Each capsule or cartridge may generally contain between 20 ⁇ g-10mg of the compound of formula (I) optionally in combination with another therapeutically active ingredient.
  • the compound of the invention may be presented without excipients.
  • Packaging of the formulation may be suitable for unit dose or multi-dose delivery.
  • the formulation can be pre- metered (eg as in Diskus, see GB 2242134 or Diskhaler, see GB 2178965, 2129691 and 2169265) or metered in use (eg as in Turbuhaler, see EP 69715).
  • An example of a unit-dose device is Rotahaler (see GB 2064336).
  • the Diskus inhalation device comprises an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet hermetically but peelably sealed thereto to define a plurality of containers, each container having therein an inhalable formulation containing a compound of formula (I) preferably combined with lactose.
  • the strip is sufficiently flexible to be wound into a roll.
  • the lid sheet and base sheet will preferably have leading end portions which are not sealed to one another and at least one of the said leading end portions is constructed to be attached to a winding means.
  • the hermetic seal between the base and lid sheets extends over their whole width.
  • the lid sheet may preferably be peeled from the base sheet in a longitudinal direction from a first end of the said base sheet.
  • Spray compositions for topical delivery to the lung by inhalation may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant.
  • Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain the compound of formula (I) optionally in combination with another therapeutically active ingredient and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, especially 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof.
  • a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, especially 1,1,1,2-tetrafluoroethan
  • the aerosol composition may be excipient free or may optionally contain additional formulation excipients well known in the art such as surfactants eg oleic acid or lecithin and cosolvents eg ethanol.
  • Pressurised formulations will generally be retained in a canister (eg an aluminium canister) closed with a valve (eg a metering valve) and fitted into an actuator provided with a mouthpiece.
  • Medicaments for administration by inhalation desirably have a controlled particle size.
  • the optimum particle size for inhalation into the bronchial system is usually 1-1 O ⁇ m, preferably 2- 5 ⁇ m. Particles having a size above 20 ⁇ m are generally too large when inhaled to reach the small airways.
  • the particles of the active ingredient as produced may be size reduced by conventional means eg by micronisation.
  • the desired fraction may be separated out by air classification or sieving.
  • the particles will be crystalline.
  • an excipient such as lactose is employed, generally, the particle size of the excipient will be much greater than the inhaled medicament within the present invention.
  • the excipient is lactose it will typically be present as milled lactose, wherein not more than 85% of lactose particles will have a MMD of 60-90 ⁇ m and not less than 15% will have a MMD of less than 15 ⁇ m.
  • Intranasal sprays may be formulated with aqueous or non-aqueous vehicles with the addition of agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants.
  • agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants.
  • Solutions for inhalation by nebulation may be formulated with an aqueous vehicle with the addition of agents such as acid or alkali, buffer salts, isotonicity adjusting agents or antimicrobials. They may be sterilised by filtration or heating in an autoclave, or presented as a non-sterile product.
  • Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
  • Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose an acacia.
  • Preferred unit dosage formulations are those containing an effective dose, as hereinbefore recited, or an appropriate fraction thereof, of the active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • the compounds and pharmaceutical formulations according to the invention may be used in combination with or include one or more other therapeutic agents, for example selected from anti-inflammatory agents, anticholinergic agents (particularly an M
  • anti-inflammatory agents for example selected from anti-inflammatory agents, anticholinergic agents (particularly an M
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with one or more other therapeutically active agents, for example selected from an anti-inflammatory agent (for example a corticosteroid or an NSAID), an anticholinergic agent, another ⁇ 2 -adrenoreceptor agonist, an antiinfective agent (e.g. an antibiotic or an antiviral), or an antihistamine.
  • an anti-inflammatory agent for example a corticosteroid or an NSAID
  • an anticholinergic agent for example a corticosteroid or an NSAID
  • an antiinfective agent e.g. an antibiotic or an antiviral
  • an antihistamine e.g. an antibiotic or an antiviral
  • PDE-4 inhibitor Preferred combinations are those comprising one or two other therapeutic agents.
  • the other therapeutic ingredient(s) may be used in the form of salts, (e.g. as alkali metal or amine salts or as acid addition salts), or prodrugs, or as esters (e.g. lower alkyl esters), or as solvates (e.g. hydrates) to optimise the activity and/or stability and/or physical characteristics (e.g. solubility) of the therapeutic ingredient.
  • the therapeutic ingredients may be used in optically pure form.
  • Suitable anti-inflammatory agents include corticosteroids and NSAIDs.
  • Suitable corticosteroids which may be used in combination with the compounds of the invention are those oral and inhaled corticosteroids and their pro-drugs which have anti-inflammatory activity. Examples include methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6 ⁇ ,9 ⁇ - difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-l 1 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-l,4-diene-l 7 ⁇ - carbothioic acid S-fluoromethyl ester, 6 ⁇ ,9 ⁇ -difluoro-l l ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-17 ⁇ - propionyloxy- androsta-l,4-diene-17 ⁇ -carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl) ester, beclomet
  • the 17-propionate ester or the 17,21-dipropionate ester the 17-propionate ester or the 17,21-dipropionate ester
  • budesonide flunisolide
  • mometasone esters e.g. the furoate ester
  • triamcinolone acetonide e.g. the furoate ester
  • rofleponide triamcinolone acetonide
  • ciclesonide butixocort propionate
  • RPR- 106541 the 17-propionate ester or the 17,21-dipropionate ester
  • ST- 126 the 17-propionate ester or the 17,21-dipropionate ester
  • flunisolide e.g. the furoate ester
  • triamcinolone acetonide e.g. the furoate ester
  • rofleponide triamcinolone acetonide
  • ciclesonide butixocort propionat
  • Preferred corticosteroids include fluticasone propionate, 6 ⁇ ,9 ⁇ -difluoro-l l ⁇ -hydroxy-16 ⁇ -methyl-17 ⁇ -[(4-methyl-l,3-thiazole-5- carbonyl)oxy]-3-oxo-androsta-l,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester and 6 ⁇ ,9 ⁇ - difluoro- 17 ⁇ -[(2-furanylcarbonyl)oxy]- 1 1 ⁇ -hydroxy- 16 ⁇ -methyl-3-oxo-androsta- 1 ,4-diene- 17 ⁇ - carbothioic acid S-fluoromethyl ester, more preferably 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2- furanylcarbonyl)oxy]- 1 1 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta- 1 ,4-diene- 17 ⁇ -carbothioic acid S-fluoromethyl ester.
  • Suitable NSAIDs include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g. adenosine 2a agonists), cytokine antagonists (e.g. chemokine antagonists) or inhibitors of cytokine synthesis.
  • Suitable other ⁇ 2 -adrenoreceptor agonists include salmeterol (e.g. as the xinafoate), salbutamol
  • the PDE4-specific inhibitor useful in this aspect of the invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family as well as PDE4.
  • a PDE4 inhibitor which has an IC50 ratio of about 0.1 or greater as regards the IC50 for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity.
  • the cAMP catalytic site which binds R and S rolipram with a low affinity is denominated the "low affinity” binding site (LPDE 4) and the other form of this catalytic site which binds rolipram with a high affinity is denominated the "high affinity” binding site (HPDE 4).
  • LPDE 4 low affinity binding site
  • HPDE 4 high affinity binding site
  • Isolated human monocyte PDE4 and hrPDE human recombinant PDE4 was determined to exist primarily in the low affinity form. Hence, the activity of test compounds against the low affinity form of PDE4 can be assessed using standard assays for PDE4 catalytic activity employing 1 ⁇ M
  • [ 3 H]-roli ⁇ ram (Torphy eLaf, J. of Biol. Chem., Vol. 267, No. 3 pp 1798- 1804, 1992).
  • the assay was run for 1 hour at 30° C.
  • the reaction was terminated and bound ligand was separated from free ligand using a Brandel cell harvester. Competition for the high affinity binding site was assessed under conditions that were identical to those used for measuring low affinity PDE activity, expect that [ 3 H]-cAMP was not present.
  • PDE activity was assayed using a [ 3 H]cAMP SPA or [ 3 H]cGMP SPA enzyme assay as described by the supplier (Amersham Life Sciences).
  • the reactions were conducted in 96-well plates at room temperature, in 0.1 ml of reaction buffer containing (final concentrations): 50 M Tris-HCI, pH 7.5, 8.3 mM MgCl 2 , 1.7 mM EGTA, [ 3 H]cAMP or [ 3 H] cGMP (approximately 2000 dpm/pmol), enzyme and various concentrations of the inhibitors.
  • the assay was allowed to proceed for 1 hr and was terminated by adding 50 ⁇ l of SPA yttrium silicate beads in the presence of zinc sulfate. The plates were shaken and allowed to stand at room temperature for 20 min. Radiolabeled product formation was assessed by scintillation spectrometry.
  • the assay was performed at 30°C for 1 hr in 0.5 ⁇ l buffer containing (final concentrations): 50 mM Tris-HCI, pH 7.5, 5 mM MgCI 2 , 0.05% bovine serum albumin, 2 nM [ 3 H]R-rolipram (5.7 x 104 dpm/pmol) and various concentrations of non- radiolabeled inhibitors.
  • the reaction was stopped by the addition of 2.5 ml of ice-cold reaction buffer (without [ 3 H]-R-rolipram) and rapid vacuum filtration (Brandel Cell Harvester) through Whatman GF/B filters that had been soaked in 0.3% polyethylenimine.
  • the filters were washed with an additional 7.5 ml of cold buffer, dried, and counted via liquid scintillation spectrometry.
  • the preferred PDE4 inhibitors of use in this invention will be those compounds which have a salutary therapeutic ratio, i.e., compounds which preferentially inhibit cAMP catalytic activity where the enzyme is in the form that binds rolipram with a low affinity, thereby reducing the side effects which apparently are linked to inhibiting the form which binds rolipram with a high affinity.
  • the preferred compounds will have an IC 50 ratio of about 0.1 or greater as regards the IC5 Q for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity.
  • a further refinement of this standard is that of one wherein the PDE4 inhibitor has an IC50 ratio of about 0.1 or greater; said ratio is the ratio of the IC5 Q value for competing with the binding of InM of [ 3 H]R-rolipram to a form of PDE4 which binds rolipram with a high affinity over the IC50 value for inhibiting the PDE4 catalytic activity of a form which binds rolipram with a low affinity using 1 ⁇ M[ 3 H]-cAMP as the substrate.
  • PDE4 inhibitors examples include: (R)-(+)-l-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone; (R)-(+)-l-(4-bromobenzyl)-4-[(3-cyclopentyIoxy)-4-methoxyphenyl]-2-pyrrolidone; 3-(cyclopentyloxy-4-methoxyphenyl)-l-(4-N'-[N2-cyano-S-methyl-isothioureido]benzyl)-2- pyrrolidone; cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-carboxylic acid]; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l-ol]
  • PDE4 inhibitors which have an IC50 ratio of greater than 0.5, and particularly those compounds having a ratio of greater than 1.0.
  • Preferred compounds are cis 4- cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-carboxylic acid, 2-carbomethoxy-4- cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l-one and c _-[4-cyano- 4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l-ol]; these are examples of compounds which bind preferentially to the low affinity binding site and which have an IC50 ratio of 0.1 or greater.
  • PDE-4 and mixed PDE3/PDE4 inhibitors include those listed in WOO 1/13953, the disclosure of which is hereby incorporated by reference.
  • Suitable anticholinergic agents are those compounds that act as antagonists at the muscarinic receptor, in particular those compounds which are antagonists of the Mi and M receptors.
  • exemplary compounds include the alkaloids of the belladonna plants as illustrated by the likes of atropine, scopolamine, homatropine, hyoscyamine; these compounds are normally administered as a salt, being tertiary amines.
  • drugs are readily available from a number of commercial sources or can be made or prepared from literature data via, to wit: Atropine - CAS-51-55-8 or CAS-51-48-1 (anhydrous form), atropine sulfate - CAS-5908-99-6; atropine oxide - CAS-4438-22-6 or its HCI salt - CAS-4574-60-1 and methylatropine nitrate - CAS-52-88-0.
  • Preferred anticholinergics include ipratropium (e.g. as the bromide), sold under the name Atrovent, oxitropium (e.g. as the bromide) and tiotropium (e.g. as the bromide) (CAS-139404-
  • methantheline (CAS-53-46-3), propantheline bromide (CAS- 50-34- 9), anisotropine methyl bromide or Valpin 50 (CAS- 80-50-2), clidinium bromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul), isopropamide iodide (CAS-71-81-8), mepenzolate bromide (U.S. patent 2,918,408), tridihexethyl chloride (Pathilone, CAS-4310-35-4), and hexocyclium methylsulfate (Tral, CAS-1 15-63-9). See also cyclopentolate hydrochloride (CAS-53-46-3), propantheline bromide (CAS- 50-34- 9), anisotropine methyl bromide or Valpin 50 (CAS- 80-50-2), clidinium bromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul), isopropamide
  • Suitable antihistamines include any one or more of the numerous antagonists known which inhibit H receptors, and are safe for human use. All are reversible, competitive inhibitors of the interaction of histamine with Hpreceptors. The majority of these inhibitors, mostly first generation antagonists, have a core structure, which can be represented by the following formula:
  • This generalized structure represents three types of antihistamines generally available: ethanolamines, ethylenediamines, and alkylamines.
  • first generation antihistamines include those which can be characterized as based on piperizine and phenothiazines.
  • Second generation antagonists which are non-sedating, have a similar structure-activity relationship in that they retain the core ethylene group (the alkylamines) or mimic the tertiary amine group with piperizine or piperidine.
  • Exemplary antagonists are as follows: Ethanolamines: carbinoxamine maleate, clemastine fumarate, diphenylhydramine hydrochloride, and dimenhydrinate.
  • Ethylenediamines pyrilamine amleate, tripelennamine HCI, and tripelennamine citrate.
  • Alkylamines chlropheniramine and its salts such as the maleate salt, and acrivastine.
  • Piperazines hydroxyzine HCI, hydroxyzine pamoate, cyclizine HCI, cyclizine lactate, meclizine HCI, and cetirizine HCI.
  • Piperidines Astemizole, levocabastine HCI, loratadine or its descarboethoxy analogue, and terfenadine and fexofenadine hydrochloride or another pharmaceutically acceptable salt.
  • Azelastine hydrochloride is yet another H] receptor antagonist which may be used in combination with a PDE4 inhibitor.
  • Examples of preferred anti-histamines include methapyrilene and loratadine.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a corticosteroid.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an antihistamine.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor and a corticosteroid.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic and a PDE-4 inhibitor.
  • compositions comprising a combination as defined above together with a physiologically acceptable diluent or carrier represent a further aspect of the invention.
  • the individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.
  • a process for preparing a compound of formula (I), (la) or (lb) or a salt, solvate, or physiologically functional derivative thereof which comprises a process (a) (b) (c) or (d) as defined below followed by the following steps in any order:
  • a compound of formula (I), (la) or (lb) may be obtained by deprotection of a protected intermediate, for example of formula (II):
  • R 1 , R 2 , R 3 , R 4 , R 5 , m, and n are as defined for the compound of formula (I), (la) or (lb)
  • R 8 , R 9 , and R 10 are each independently either hydrogen or a protecting group provided that at least one of R 8 , R 9 , and R 10 is a protecting group
  • R 14 is either hydrogen or a protecting group.
  • Suitable protecting groups may be any conventional protecting group such as those described in
  • R 8 and R 9 are esters such as acetate ester, aralkyl groups such as benzyl, diphenylmethyl, or triphenylmethyl, and tetrahydropyranyl.
  • suitable amino protecting groups represented by R'° include benzyl, ⁇ -methylbenzyl, diphenylmethyl, triphenylmethyl, benzyloxycarbonyl, tert-butoxycarbonyl, and acyl groups such as trichloroacetyl or trifluoroacetyl.
  • protecting groups may include orthogonal protection of groups in the compounds of formula (II) to facilitate the selective removal of one group in the presence of another, thus enabling selective functionalisation of a single amino or hydroxyl function.
  • the -CH(OH) group may be orthogonally protected as -CHOR 14 using, for example, a trialkylsilyl group such as triethylsilyl.
  • a trialkylsilyl group such as triethylsilyl.
  • orthogonal protection strategies available by conventional means as described in Theodora W Greene (see above).
  • the deprotection to yield a compound of formula (I), (la) or (lb) may be effected using conventional techniques.
  • R 8 , R 9 , and/or R 10 is an aralkyl group, this may be cleaved by hydrogenolysis in the presence of a metal catalyst (e.g. palladium on charcoal).
  • a metal catalyst e.g. palladium on charcoal
  • R 8 and/or R 9 When R 8 and/or R 9 is tetrahydropyranyl this may be cleaved by hydrolysis under acidic conditions.
  • Acyl groups represented by R 10 may be removed by hydrolysis, for example with a base such as sodium hydroxide, or a group such as trichloroethoxycarbonyl may be removed by reduction with, for example, zinc and acetic acid. Other deprotection methods may be found in Theodora W Greene (see above).
  • R 8 and R 9 may together represent a protecting group as in the compound of formula (III).
  • R 11 and R 12 are independently selected from hydrogen, . 6 alkyl, or aryl. In a preferred aspect, both R 11 and R 12 are methyl.
  • a compound of formula (III) may be converted to a compound of formula (I), (la) or (lb) by hydrolysis with dilute aqueous acid, for example acetic acid or hydrochloric acid in a suitable solvent or by transketalisation in an alcohol, for example ethanol, in the presence of a catalyst such as an acid (for example, toluenesulphonic acid) or a salt (such as pyridinium tosylate) at normal or elevated temperature.
  • a catalyst such as an acid (for example, toluenesulphonic acid) or a salt (such as pyridinium tosylate) at normal or elevated temperature.
  • protecting groups R 8 , R 9 , R 10 and R 14 may be removed in a single step or sequentially.
  • the precise order in which protecting groups are removed will in part depend upon the nature of said groups and will be readily apparent to the skilled worker.
  • this protecting group is removed together with any protecting group on the CH(OH) moiety, followed by removal of R 10 .
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 m, and n are as defined for the compound of formula (II) or (III).
  • a compound of formula (IV) to a compound of formula (II) or (III) may be effected by treatment with a base, for example a non-aqueous base, such as potassium trimethylsilanoate, or an aqueous base such as aqueous sodium hydroxide, in a suitable solvent such as tetrahydrofuran.
  • a base for example a non-aqueous base, such as potassium trimethylsilanoate, or an aqueous base such as aqueous sodium hydroxide, in a suitable solvent such as tetrahydrofuran.
  • R 1 , R 2 , and R 3 are as defined for the compound of formula (IV) and L is a leaving group, such as a halo group (typically, bromo or iodo) or a sulphonate ester such as a haloalkyl sulphonate (typically, trifluoromethanesulphonate), followed by reduction.
  • L is a leaving group, such as a halo group (typically, bromo or iodo) or a sulphonate ester such as a haloalkyl sulphonate (typically, trifluoromethanesulphonate), followed by reduction.
  • the coupling of compound of formula (V) with a compound of formula (VI) is conveniently effected in the presence of a catalyst system such as bis (triphenylphosphine) palladium dichloride with an organic base such as a trialkylamine, for example, triethylamine, in a suitable solvent, for example acetonitrile or dimethylformamide.
  • a catalyst system such as bis (triphenylphosphine) palladium dichloride with an organic base such as a trialkylamine, for example, triethylamine
  • a suitable solvent for example acetonitrile or dimethylformamide.
  • the resulting alkyne may then be reduced, either with or without being isolated to form the compound of formula (IV).
  • the reduction may be effected by any suitable method such as hydrogenation in the presence of a catalyst, for example, palladium/charcoal or platinum oxide.
  • R 1 , R 2 , and R 3 may represent groups convertible into R 1 , R 2 , and R 3 , for example halo groups. This is particularly useful where one of the groups R 1 , R 2 , and R 3 may be affected by any of the subsequent transformations. Thus, for example, where R 1 contains an alkenylene moiety, this is preferably introduced after the reduction of the alkyne formed by reaction of compounds (V) and (VI).
  • R , R , m and n are as defined for the compound of formula (V) and L 1 is a leaving group, for example a halo group (typically bromo or iodo) or a sulphonate such as an alkyl sulphonate (typically, methanesulphonate), an arylsulphonate (typically, toluenesulphonate), or a haloalkyl sulphonate (typically, trifluoromethanesulphonate).
  • a halo group typically bromo or iodo
  • a sulphonate such as an alkyl sulphonate (typically, methanesulphonate), an arylsulphonate (typically, toluenesulphonate), or a haloalkyl sulphonate (typically, trifluoromethanesulphonate).
  • the coupling of a compound of formula (VII) with a compound of formula (VIII) may be effected in the presence of a base, such as a metal hydride, for example sodium hydride, or an inorganic base such as cesium carbonate, in an aprotic solvent, for example dimethylformamide.
  • a base such as a metal hydride, for example sodium hydride, or an inorganic base such as cesium carbonate
  • Compounds of formula (VIII) may be prepared from the corresponding dihaloalkane and hydroxyalkyne by conventional chemistry, typically in the presence of an inorganic base, such as aqueous sodium hydroxide, under phase transfer conditions in the presence of a salt such as tetraalkylammonium bromide.
  • an inorganic base such as aqueous sodium hydroxide
  • R 8 and R 9 are as defined for the compound of formula (VII) and R 13 is for example tert-butyl, or aryl, for example phenyl.
  • the ring closure may be effected by treatment with a base, such as a metal hydride, for example sodium hydride, in the presence of an aprotic solvent, for example, dimethylformamide.
  • R 8 and R 9 and R 13 are as defined for the compound of formula (IX), by reduction by any suitable method, for example by treatment with borane, in the presence of a chiral catalyst, such as CBS-oxazaborolidine, in a suitable solvent such as tetrahydrofuran.
  • a chiral catalyst such as CBS-oxazaborolidine
  • the compound of formula (X) may be prepared from the corresponding halide of formula (XI)
  • R 8 and R 9 are as defined for the compound of formula (X) and Y is halo, suitably bromo.
  • the conversion of a compound of formula (XI) to a compound of formula (X) may be effected by reaction with the protected amine HN(COOR 13 ) 2 wherein R 13 is as defined for the compound of formula (X) in the presence of an inorganic base such as cesium carbonate, followed by selective removal of one of the COOR 13 groups, for example by treatment with an acid such as trifluoroacetic acid.
  • an inorganic base such as cesium carbonate
  • Compounds of formula (XI) may be prepared from the corresponding compound having free hydroxymethyl and hydroxy substituents (which itself may be prepared from 2-bromo- 1 -(4- hydroxy)-3-hydroxymethyl-phenethyl)ethanone, the preparation of which is described in GB2140800, by treatment with 2-methoxypropane in acetone in the presence of an acid e.g. p- toluene-sulphonic acid in a nitrogen atmosphere or by other standard methods) by forming the protected groups R 8 OCH 2 - and R 9 0- wherein R 8 and R 9 are as defined for the compound of formula (XI). Such methods are described in DE 3513885 (Glaxo).
  • a compound of formula (I) , (la) or (lb) may be obtained by alkylation of an amine of formula (XII):
  • R 8 , R 9 , R 10 and R 14 are each independently either hydrogen or a protecting group. Suitable protecting groups are discussed in the definition of compounds of formula (II);
  • R 1 , R 2 , R 3 , R 4 , R 5 , m, and n are as defined for the compound of formula (I), (la) or (lb) and L 2 is a leaving group such as halo (typically bromo); followed by removal of any protecting groups present by conventional methods as described above for the deprotection of compounds of formula (II).
  • reaction of compounds of formulae (XII) and (XIII) is optionally effected in the presence of an organic base such as a trialkylamine, for example, diisopropylethylamine, and in a suitable solvent for example dimethyl formamide.
  • organic base such as a trialkylamine, for example, diisopropylethylamine, and in a suitable solvent for example dimethyl formamide.
  • Compounds of formula (XII) are known in the art (for example EP-A 0947498) or may be readily prepared by a person skilled in the art.
  • Compounds of formula (XIII) may be prepared by coupling a compound of formula (VI) as defined above, or a precursor thereof (wherein one or more of the substituents R 1 , R 2 or R 3 is a group which is convertible to the desired group R 1 , R 2 , or R 3 ) with a compound of formula (VIII) as shown above wherein R 4 , R 5 , m, and n are as defined for the compound of formula (XIII) and L 1 is a leaving group as defined above.
  • substituents R , R , and/or R 3 may be formed by conventional conversions where a precursor is present.
  • An alkyne of formula (XIV) may also be prepared by reacting a compound of formula (XV):
  • XX with a compound of formula (VI) using methods analogous to those described above for coupling a compound (V) with a compound (VI).
  • a compound of formula (I) (la) or (lb) may be prepared by reacting a compound of formula (XVII):
  • the reaction may be effected using conventional conditions for such displacement reactions.
  • Compounds of formula (XVIII) may be prepared by reacting a compound of formula (XIII) with an amine R I0 NH 2 .
  • a compound of formula (I), (la) or (lb) may be prepared by removal of a chiral auxiliary from a compound of formula (Ha):
  • R 1 - R 5 , R 8 , R 9 , m and n are as hereinbefore defined and R 15 represents a chiral auxiliary.
  • a “chiral auxiliary” is a moiety that is introduced into a molecule to influence the stereochemistry of the product formed, and is removed in whole or part at a later time.
  • a chiral auxiliary may simultaneously function as a protecting group.
  • Chiral auxiliaries are commercially available, and persons skilled in the art would choose one based on the properties desired i.e. the absolute stereochemistry desired and compatibility with the processes being used.
  • Chiral auxiliaries suitable for use in this process include but are not limited to the S-isomer and/or the R-isomer of phenyl glycinol and substituted derivatives thereof.
  • the chiral auxiliary is preferably a moiety of the formula:
  • R 16 represents C ⁇ alkyl or optionally substituted phenyl or benzyl wherein the optional substitution is one or more independently selected from halogen, hydroxy, or nitro e.g. para-hydroxyphenyl.
  • chiral auxiliary is a moiety:
  • R 16 is as defined above. Alternatively it may be a moiety of formula:
  • R 16 is as defined above.
  • R 16 represents phenyl optionally substituted as described above, Most preferably R represents unsubstituted phenyl.
  • the chiral auxiliary in this process may typically be removed by hydrogenolysis using for example a palladium on carbon catalyst or preferably using palladium hydroxide (Pearlman's catalyst).
  • a palladium on carbon catalyst or preferably using palladium hydroxide (Pearlman's catalyst).
  • Pearlman's catalyst the removal of the chiral auxiliary is most efficient. This method of removal is especially suitable where R 1 is phenyl or a substituted phenyl.
  • the nitrogen, to which the auxiliary is attached may be derivatised under oxidising conditions to form the N-oxide before elimination by heating to give a secondary amine.
  • a compound of formula (Ila) may be prepared by reduction of the corresponding alkyne of formula (XIX):
  • the protecting groups R 8 and R 9 together form a group -CR n R 12 - as in the compounds of formula (III).
  • Reduction of an alkyne of formula (XIX) may be effected by methods well known in the art, for example by catalytic hydrogenation, using palladium on charcoal or more preferably palladium hydroxide (Pearlman's catalyst).
  • the chiral auxiliary may also be removed under reductive conditions.
  • the reduction of the alkyne and removal of the chiral auxiliary may be effected concomitantly in a 'one-pot' reaction.
  • An alkyne of formula (XIX) may be prepared by reaction of a compound of formula (XX)
  • a compound of formula (XX) may be prepared by reacting a compound of formula (Xlla):
  • An aldehyde of formula (XXI) may be prepared from a corresponding halide of formula (VIII) using standard techniques such as treatment with sodium bicarbonate in a solvent such as DMSO at elevated temperature, preferably in the range 130-160 ° C.
  • a compound of formula (Xlla) may be prepared from a compound of formula (XXII):
  • R 8 , R 9 and R 15 are as hereinbefore defined by treatment with a reducing agent such as a hydride source e.g. sodium borohydride.
  • a reducing agent such as a hydride source e.g. sodium borohydride.
  • this process takes place in the presence of an inert metal salt such as calcium chloride suitably at non-extreme temperatures e.g. below ambient, such as 0°C.
  • an inert metal salt such as calcium chloride suitably at non-extreme temperatures e.g. below ambient, such as 0°C.
  • a compound of formula (XXII) may be prepared from a compound of formula (XI) as hereinbefore defined by reaction with an appropriate chiral amine, e.g. (S)-phenylglycinol, in the presence of a non-nucleophilic base in an inert solvent at non-extreme temperatures.
  • an appropriate chiral amine e.g. (S)-phenylglycinol
  • the precise order of the synthetic steps by which the various groups and moieties are introduced into the molecule may be varied. It will be within the skill of the practitioner in the art to ensure that groups or moieties introduced at one stage of the process will not be affected by subsequent transformations and reactions, and to select the order of synthetic steps accordingly.
  • the enantiomeric compounds of the invention may be obtained (i) by separation of the components of the corresponding racemic mixture, for example, by means of a chiral chromatography column, enzymic resolution methods, or preparing and separating suitable diastereoisomers, or (ii) by direct synthesis from the appropriate chiral intermediates by the methods described above.
  • Optional conversions of a compound of formula (I), (la) or (lb) to a corresponding salt may conveniently be effected by reaction with the appropriate acid or base.
  • Optional conversion of a compound of formula (I), (la) or (lb) to a corresponding solvate or physiologically functional derivative may be effected by methods known to those skilled in the art.
  • the present invention provides novel intermediates for the preparation of compounds of formula (I), (la) or (lb), for example: compounds of formula (II) and (III) as defined above, or an optical isomer, a salt, or a protected derivative thereof; particularly, a compound selected from:
  • Silica gel refers to Merck silica gel 60 Art number 7734.
  • Flash silica gel refers to Merck silica gel 60 Art number 9385.
  • Biotage refers to prepacked silica gel cartridges containing KP-Sil run on flash 12i chromatography module.
  • Bond Elut are prepacked cartridges used in parallel purifications, normally under vacuum. These are commercially available from Varian.
  • LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4.6 mm ID) eluting with 0.1% HC0 2 H and 0.01 M ammonium acetate in water (solvent A), and 0.05% HC0 2 H 5% water in acetonitrile (solvent B), using the following elution gradient 0-0.7 min 0%B, 0.1-4.2 min 100%B, 4.2-5.3 min 0%B, 5.3-5.5 min 0%B at a flow rate of 3 ml/min.
  • the mass spectra were recorded on a Fisons VG Platform spectrometer using electrospray positive and negative mode (ES+ve and ES-ve).
  • the XRPD analysis shown in the Figures were performed on a Phillips X'pert Pro powder diffractometer, Model PW3040/60, serial number DY1379. The method runs from 2 to 45 degrees 2Theta with 0.02 degree 2Theta step size and a 2 second collection time at each step.
  • Example 1 3-(4-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyl]ethyl>amino)- hexyl]oxy ⁇ butyl)benzenesulfonamide acetate
  • Cesium carbonate (70.4g) was added to a stirred suspension of 2-bromo-l-(2,2-dimethyl-4H-l,3- benzodioxin-6-yl)ethanone, (Glaxo, DE 3513885, 1985) (61.8g) and di-t-butyl iminodicarboxylate (47.15g) in acetonitrile (600ml) under nitrogen.
  • Example 4 3-(4-(r6-( ⁇ ( " 2RV2-Hvdroxy-2-r4-hvdroxy-3-( ' hvdroxymethyl)phenyl1ethvU- amino)hexyl]oxy .
  • butvD-N-methylbenzenesulfonamide acetate i_ 3-r4-(l6-r(5RV5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl.-2-oxo-1.3-oxazolidin-3- yl]hexyl > oxy)but- 1 -ynyll-N-methylbenzenesulfonamide was prepared using methods similar to those described in Example 1 vii.
  • Example S 2-(Hvdroxymethyl)-4- ⁇ (lR)-l-hydroxy-2-r_6- .4-r3-(morpholin-4- ylsulfonyOphenvUbutoxylhexyOaminolethvU phenol acetate iU5RV5- .2-Dimethyl-4H-1.3-benzodioxin-6-vn-3-r6-f (4-r3-(morpholin-4- ylsulfony ⁇ phenyl1but-3-vnyl>oxy)hexyl]-1.3-oxazolidin-2-one was prepared using methods similar to those described in Example 1 vii.
  • Example 6 3-(4- ⁇ r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hydroxymethyl)phenyl]ethyl. - amino)hexyl]oxylbutyl)-N.N-dimethylbenzenesulfonamide acetate i) 3-r4-((6-r( " 5RV5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-vn-2-oxo-1.3-oxazolidin-3- yl]hexyl ⁇ oxy,but-l-ynyl]-N,N-dimethylbenzenesulfonamide
  • Example 7 3-(4- ⁇ r6-( ⁇ (2RV2-Hvdroxy-2-r4-hvdroxy-3-(hydroxymethyl)phenyl]ethyl ⁇ - amino)hexyl]oxy)butyl)-N-isopropylbenzenesulfonamide acetate i . 3-r4-.
  • Example 8 N-,tert-Butyl.-3-.4- . r6-f .f2R)-2-hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl]ethy amino)hexyl]oxylbutyl)benzenesulfonamide acetate i .
  • Example 9 2-(Hvdroxymethyl)-4- ⁇ f lR ' )-l-hvdroxy-2-r(6- ⁇ 4-[3-fpiperidin-l- ylsulfonyl)phenyl1butoxy ⁇ hexyl)amino]ethy phenol acetate i .5RV5-( , 2.2-Dimethyl-4H-1.3-benzodioxin-6-vn-3-r6-( ' (4-r3-( ' piperidin-l- ylsulfonyl)phenyribu.-3-ynyl . oxy,hexyl]-1.3-oxazolidin-2-one was prepared using methods similar to those described in Example 6 i. ES+ve 625 (MH) + .
  • Example 10 l-.3-(4- ..6-( .(2R.-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl]ethy amino,-hexyl1oxy)butyl)phenyl]methanesulfonamide i , Sodium (3-iodophenyl)methanesulfonate
  • Example 11 3-, 5- . r5-( ⁇ (2R)-2-Hydroxy-2-r4-hvdroxy-3-
  • Example 13 3- .6-r4- ⁇ .2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl)phenyllethv ⁇ amino)butoxy]hexyl.
  • Example 14 4-.3-(4- . r6-( ' ,( ' 2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethvDphenyllethyl ⁇ amino .hexylloxy) butvDphenyl] butane- 1 -sulfonamide i) 4-(3-Iodophenyl)butyl methanesulfonate
  • Example 19 N-r3-(Aminosulfonyl)phenvn-3-( , 4-(r6- (2R)-2-hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl]ethyl)amino)hexyl]oxy ⁇ butyl)benzenesulfonamide acetate N-r3-(Aminosulfonyl)phenyl1-3-r4-((6-r(5R)-5-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo- 1.3-oxazolidin-3-yl]hexyl)oxy)but-l -vnyl]benzenesulfonamide was prepared using methods similar to those described in Example 1 vii.
  • LCMS RT 2.95min, ES+ve 650 (MH) + .
  • Example 22 N-Benzyl-3-(4- . r6-( , .(2R)-2-hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl)phenyl]ethv ⁇ amino)hexynoxy>butyl)benzenesulfonamide acetate i) N-Benzyl-3-r4-. ⁇ 6-r(5R)-5-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yllhexyl ) oxy)but- 1 -ynyl] benzenesulfonamide was prepared using methods similar to those described in Example 6 i. ES+ve 647 (MH) +
  • N-benzyl-3 -(4- , ⁇ 6-( . , 2R)-2-hvdroxy-2-r4-hvdroxy-3 - was prepared using methods similar to those described in Example 1 x.
  • LCMS RT 2.72 min,
  • Ethyl isocyanate (0.015g) was added to a stirred mixture of 3-[4-( ⁇ 6-[(5R)-5-(2,2-dimethyl-4H- l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3-yl]hexyl ⁇ oxy)butyl]benzenesulfonamide (0.1 lg) and K 2 C0 3 (0.055g) in acetone (2ml). The mixture was heated at reflux for 2h then ethyl isocyanate (0.005g) was added. After 0.5h the reaction mixture was cooled and quenched with water (lml). The mixture was partitioned between EtOAc (20ml) and H 2 0 (20ml). The aqueous phase was extracted with EtOAc (20ml). The combined EtOAc phases were washed with brine
  • Example 25 3-(4- ⁇ r6-( ,( , 2S)-2-Hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl ,phenyl]ethyl)amino)hexyl ⁇ oxy ⁇ buWl)benzenesulfonamide acetate
  • Example 26 N-I -. .1X4- . re-f .dR. ⁇ -Hvdroxy ⁇ -K-hvdroxy-S- acetate i) N-(4-r. (3-r4-f(6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl1hexyl)oxy)but-l-vnyllphenyl>sulfonyl)amino]phenyl ⁇ acetamide was prepared using methods similar to those described in Example 1 vii. ES-ve 688 (M-HV
  • Example 27 N-Cvclobutyl-3-.4- . r6-( _(2R)-2-hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl)phenyl]ethv amino)hexyl]oxy>butyl)benzenesulfonamide acetate (i) N-Cvclobutyl-3-r4-((6-r(5R)-5-.2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3- oxazolidin-3-yl]hexyl ⁇ oxy)but-l-ynyl]benzenesulfonamide was prepared using methods similar to those described in Example 1 vii. ES+ve 61 1 (MH) +
  • Example 28 N-Cvclohexyl-3-.4- ⁇ r6-( ,(2R)-2-hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl]ethyl , amino)hexyl]oxy. butyl)benzenesulfonamide acetate i) N-Cyclohexyl-3 - ⁇ 4-( j 6- .
  • Example 30 N-r2-(2-Hvdroxyethoxy)ethyll-3-(4-(r6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl)phenyl]ethyl . amino)hexyl]oxylbutyl)benzenesulfonamide i) 3-[4-( ⁇ 6-[(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexyl .
  • Example 31 N-(4-Fluorophenyl)-3-(4- ⁇ r6-( .(2R)-2-hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl )phenyll ethyl > am i no)hexyll oxy ⁇ butvDbenzenesulfonamide acetate i) 3-[4-( ⁇ 6- (5R)-5-(2,2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexyl . oxy)but-l-vnyll-N-(4-fluorophenyl)benzenesulfonamide was prepared using methods similar to those described in Example 1 vii. ES+ve 651 (MH) +
  • Example 32 N-r4-(Aminosulfonyl)phenyl1-3-.4-(r6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl1ethyl)amino)hexyl]oxy, butyl)benzenesulfonamide acetate i) N-r4-.Aminosulfonyl)phenyll-3-r4-( ' ⁇ 6-r(5R)-5-( ' 2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2- oxo-1.3-oxazolidin-3-yl1hexy ⁇ oxy)but-l-vnyl]benzenesulfonamide was prepared using methods similar to those described in Example 1 vii.
  • Example 33 2-(Hvdroxymethyl)-4- ⁇ ( 1 R)- 1 -hvdroxy-2-r(6- , 4-f 3-(piperazin- 1 - ylsulfonyl)phenyl]butoxylhexyl)aminolethvU phenol acetate i) .5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-3-r6-(l4- 3-fpiperazin-l- ylsulfonyl)phenyllbut-3-ynv oxy)hexyl1-l,3-oxazolidin-2-one was prepared using methods similar to those described in Example 1 vii. ES+ve 626 (MH) +
  • Example 34 3-C4- . f6-( , ((2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl)phenyl]ethy amino)hexyl1oxylbutyl)-N-fl-methyl-l- phenylethyDbenzenesulfonamide acetate i) 3-r4-r(6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexy oxy)but- 1 -ynyl]-N-( 1 -methyl- 1 -phenylethyDbenzenesulfonamide was prepared using methods similar to those described in Example 1 vii. ES-ve 673 (M-HV
  • Example 35 5-f4-(r6-( ' (f2R)-2-Hvdroxy-2-r4-hvdroxy-3-fhvdroxymethvD- phenv ⁇ ethyl _ amino)hexyl1oxy_ butyl)-2-methoxybenzenesulfonamide acetate i) 5-r4-( ⁇ 6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexyl . oxy)but- 1 -vnyl]-2-methoxybenzenesulfonamide was prepared using methods similar to those described in Example 1 vii. ES+ve 587 (MH) +
  • Example 36 (E)-2-f3-(4- ⁇ r6-( .(2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl)phenyllethyUamino)hexyl]oxy ⁇ butyl)phenyl]-N-methylethenesulfonamide i) 4-(3-Bromophenyl)but-3-yn- 1 -ol
  • Di-tert-butyldicarbonate (8.62g) was added to a stirred, cooled (ice bath) solution of ethenesulphonamide (S. Hirooka, Bull. Chem. Soc. Jpn. 1991, 64, 1431) (3.4g ), 4- (dimethylamino)pyridine (410mg) and triethylamine (7ml) in dichloromethane (40ml) under nitrogen.
  • the solution was stirred for 30min, washed with 2M hydrochloric acid (30ml), water
  • Example 39 3-(4- ⁇ r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethyl)- amino)hexyl]oxy, butyl)-5-pentylbenzenesuIfonamide acetate i) tert-Butyl ⁇ 3-r4-((6-r(5R)-5-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl] hexyl ) oxy)but- 1 -ynyl] -5 -pent- 1 -ynylphenyl ⁇ sulfonyl ⁇ [2- (trimethylsilyl)ethoxy]methyDcarbamate
  • the mixture was cooled to 5°C and then treated portionwise with the diazonium salt prepared above. After stirring at room temperature for lh ice (50g) was added. The mixture was extracted with ether (100ml) and the organic phases washed with NaHC0 3 solution (2 100ml) then water ( 100ml), dried ( MgS0 4 ) and concentrated. The residue was dissolved in THF (30ml) at 0°C and aqueous ammonia (0.880; 5ml) was added. After stirring at room temperature the mixture was partitioned between EtOAc (100ml) and water (100ml). The organic phase was washed with brine (50ml), dried (MgS0 4 ) and concentrated.
  • Example 42 5-(4- . r6-( .(2R)-2-Hydroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl]ethyUamino)hexyl]oxy)butyD-3-trifluoromethylbenzenesulfonamide
  • 3-Bromo-5-trifluoromethylbenzenesulfonamide was prepared using methods similar to those described in Example i. ES-ve 302,304 (M-H) "
  • Example 44 N- ..3-(4- . r6-( .(2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl)phenvHethvUamino)hexyHoxy)butyl)phenyllsulfonyl ⁇ glycine acetate
  • Cinnamic acid 0.3g was added to a solution of 3-(4- ⁇ [6-( ⁇ (2R)-2-Hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl ⁇ amino)hexyl]oxy ⁇ butyl)benzenesulfonamide (l .Og) in methanol
  • Example 47 3-(3- ⁇ .7-( .(2R)-2-Hvdroxy-2-.4-hvdroxy-3- (hvdroxymethvDphenyllethyl ⁇ amino)heptyl1oxy>propyl)benzenesulfonamide
  • Cuprous iodide (0.0 lg) and dichlorobis(triphenylphosphine)palladium (0.02g) were added and the stirring continued for 2h.
  • the solution was evaporated to dryness and applied to a Bond Elut cartridge (5g) in dichloromethane.
  • the cartridge was eluted with dichloromethane and diethyl ether to give the title compounds (0.165g), LCMS RT 3.93min (bromide) and 4.02min (iodide).
  • reaction mixture was extracted with ether and the organic layer was washed with 2M HCI, NaHC0 3 , brine, dried (MgS0 4 ). The solvent was removed by evaporation and the residue was chromatographed on a Biotage column eluting with diethyl ether-petrol (40-60°C)
  • Example 50 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -[(2-furanylcarbonvDoxy]-l l ⁇ -hvdroxy-16 ⁇ -methyl-3-oxo- androsta-l,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester Unsolvated Form 1
  • the resulting solid was collected by filtration, washed successively with 3.5% aqueous sodium hydrogen carbonate solution, water, IM hydrochloric acid, and water and dried in vacuo at 60 °C to give a cream coloured solid.
  • the dichloromethane filtrate was washed successively with 3.5% sodium hydrogen carbonate solution, water, IM hydrochloric acid, water, dried (Na 2 S0 4 ) and evaporated to give a cream coloured solid which was combined with that isolated above.
  • the combined solids (26.9g) were suspended in acetone (450ml) and stirred. Diethylamine (16.8ml, 162mmol) was added and the mixture stirred at room temperature for 4.5h.
  • a suspension of the product of part (a) (2.5g, 4.94mmol) was dissolved in anhydrous N, N- dimethylformamide (25ml) and sodium hydrogen carbonate (465mg, 5.53mmol) was added. The mixture was stirred at -20°C and bromofluoromethane (0.77ml, 6.37mmol) was added and the mixture was stirred at -20°C for 2h. Diethylamine (2.57ml, 24.7mmole) was added and the mixture stirred at -20°C for 30min. The mixture was added to 2M hydrochloric acid (93ml) and stirred for 30min.
  • Example 51 6 ⁇ .9 ⁇ -Difluoro-l l ⁇ -hvdroxy-16 ⁇ -methyl-17 ⁇ -[(4-methyl-l,3-thiazole-5- carbonyl)oxy1-3-oxo-androsta-l,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester
  • Example 51 was prepared using a method analogous to that described for Example 50: LCMS retention time 3.51min, m/z 570 MH +
  • BIOLOGICAL ACTIVITY The potencies of the aforementioned compounds were determined using frog melanophores transfected with the human beta 2 adrenoreceptor. The cells were incubated with melatonin to induce pigment aggregation. Pigment dispersal was induced by compounds acting on the human beta 2 adrenoreceptor. The beta 2 agonist activity of test compounds was assessed by their ability to induce a change in light transmittance across a melanophore monolayer (a consequence of pigment dispersal). At the human beta 2 adrenoreceptor, compounds of examples 1- 49 had IC 50 values below 1 ⁇ M.
  • Potency at other beta adrenoreceptor subtypes was determined using Chinese hamster ovary cells transfected with either the human beta 1 adrenoreceptor or the human beta 3 adrenoreceptor. Agonist activity was assessed by measuring changes in intracellular cyclic AMP.

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Abstract

The present invention relates to novel compounds of Formula (I), to a process for their manufacture, to pharmaceutical compositions containing them, and to their use in therapy, in particular their use in the prophylaxis and treatment of respiratory diseases.

Description

PHENETHANOLAMINE DERIVATIVES FOR TREATMENT OF RESPIRATORY DISEASES
The present invention is concerned with phenethanolamine derivatives, processes for their preparation, compositions containing them and their use in medicine, particularly in the prophylaxis and treatment of respiratory diseases.
Certain phenethanolamine compounds are known in the art as having selective stimulant action at β2-adrenoreceptors and therefore having utility in the treatment of bronchial asthma and related disorders. Thus GB 2 140 800 describes phenethanolamine compounds including 4- hydroxy-α'-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-l,3-benzenedimethanol l-hydroxy-2- naphthalenecarboxylate (salmeterol xinafoate) which is now used clinically in the treatment of such medical conditions.
Although salmeterol and the other commercially available β2-adrenoreceptor agonists are effective bronchodilators, the maximum duration of action is 12 hours, hence twice daily dosing is often required. There is therefore a clinical need for compounds having potent and selective stimulant action at β2.adrenoreceptors and having an advantageous profile of action.
According to the present invention, there is provided a compound of formula (I)
Figure imgf000002_0001
or a salt, solvate, or physiologically functional derivative thereof, wherein:
m is an integer of from 2 to 8; n is an integer of from 3 to 1 1 , preferably from 3 to 7; with the proviso that m + n is 5 to 19, preferably 5 to 12;
R1 is -XS02NR6R7
wherein X is -(CH )P- or C2-e alkenylene; R6 and R7 are independently selected from hydrogen,
Figure imgf000002_0002
C3.7cycloalkyl, C(O)NR8R9, phenyl, and phenyl (C^alkyl)-, or R6 and R7, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7- membered nitrogen containing ring, and R6 and R7 are each optionally substituted by one or two groups selected from halo, C,.6alkyl, C,.6haloalkyl, C,.6alkoxy, hydroxy-substituted C,.6alkoxy, -C02R8, -S02NR8R9, -CONR8R9, -NR8C(0)R9, or a 5-, 6- or 7-membered heterocylic ring; R8 and R9 are independently selected from hydrogen, Cι_6alkyl, C3.6cycloalkyl, phenyl, and phenyl (C alkyl)-; and p is an integer of from 0 to 6, preferably from 0 to 4;
R2 and R3 are independently selected from hydrogen,
Figure imgf000003_0001
halo, phenyl, and C|.6haloalkyl; and
R4 and R5 are independently selected from hydrogen and C]. alkyl with the proviso that the total number of carbon atoms in R4 and R5 is not more than 4.
In the compounds of formula (I) the group R1 is preferably attached to the meta-position relative to the -0-(CH2)n- link.
R1 preferably represents -S02NR6R7 wherein R6 and R7 are independently selected from hydrogen and
Figure imgf000003_0002
more preferably R1 is -SO2NH2.
R4 and R5 are preferably independently selected from hydrogen and methyl, more preferably R4 and R5 are both hydrogen.
m is suitably 4, 5, or 6, and n is suitably 3, 4, 5 or 6. Preferably m is 5 or 6 and n is 3 or 4, such that m + n is 8, 9 or 10, preferably 9.
According to a preferred aspect of the invention, there is provided a compound of formula (la)
Figure imgf000003_0003
or a salt, solvate, or physiologically functional derivative thereof, wherein
R1 is as defined above for formula (I).
According to a further preferred aspect of the invention, there is provided a compound of formula (lb)
Figure imgf000003_0004
or a salt, solvate, or physiologically functional derivative thereof, wherein
R1 is as defined above for formula (I).
In the compounds of formulae (la) and (lb), the group R1 is preferably attached to the rneta- position relative to the -0-(CH2)n-, -O-(CH2) - or -0-(CH2)3- link respectively.
In the compounds of formulae (la) and (lb), R1 is preferably -S02NR6R7 wherein R6 and R7 are independently selected from hydrogen and
Figure imgf000004_0001
more preferably R1 is -SO2NH2.
It is to be understood that the present invention covers all combinations of particular and preferred groups described hereinabove.
Preferred compounds of the invention include:
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}butyl)benzenesulfonamide;
4-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}butyl)benzenesulfonamide; 2-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}butyl)benzenesulfonamide;
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}butyl)-N-methylbenzenesulfonamide;
2-(Hydroxymethyl)-4-{(lR)-l-hydroxy-2-[(6-{4-[3-(morpholin-4-ylsulfonyl)- phenyl]butoxy}hexyl)amino]ethyl}phenol;
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}butyl)-N,N-dimethylbenzenesulfonamide;
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}butyl)-N-isopropylbenzenesulfonamide; N-(tert-Butyl)-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]- ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;
2-(Hydroxymethyl)-4-{(l R)-l-hydroxy-2-[(6-{4-[3-(piperidin-l-ylsulfonyl)phenyl]- butoxy}hexyl)amino]ethyl}phenol; l-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)- hexyl]oxy } butyl)phenyl]methanesulfonamide;
3-(5-{[5-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)pentyl]oxy}pentyl)benzenesulfonamide;
3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)heptyl]oxy}propyl)benzenesulfonamide; 3-{6-[4-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)butoxy]hexyl}benzenesulfonamide;
4-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}butyl)phenyl]butane-l-sulfonamide; 3-(5-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}pentyl)benzenesulfonamide;
3-(6-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}hexyl)benzenesulfonamide; 3-(3-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}propyl)benzenesulfonamide;
3-(4-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)pentyl]oxy}butyl)benzenesulfonamide;
1 -[2-(4- { [6-( {(2R)-2-Hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]methanesulfonamide;
1 -[4-(4- { [6-( {(2R)-2-Hydroxy-2-[4-hydroxy-3 -
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]methanesulfonamide;
N-[3-(Aminosulfonyl)phenyl]-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide; N-Benzyl-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;
4- {( 1 R)-2-[(6- {4-[3-( { [(Ethylamino)carbonyl]amino} sulfonyl)phenyl]butoxy } -hexyl)amino]- 1 - hydroxyethyl} - 1 -hydroxy-2-(hydroxymethyl)benzene;
3-(4-{[6-({2-Hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;
3-(4-{[6-({(2S)-2-Hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;
N-[4-({[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}butyl)phenyl]sulfonyl}amino)phenyl]acetamide N-Cyclobutyl-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;
N-Cyclohexyl-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}butyl)-N-(2-morpholin-4-ylethyl)benzenesulfonamide;
N-[2-(2-Hydroxyethoxy)ethyl]-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;
N-(4-Fluorophenyl)-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide; N-[4-(Aminosulfonyl)phenyl]-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;
2-(Hydroxymethyl)-4- {( 1 R)- 1 -hydroxy-2-[(6- {4-[3 -(piperazin- 1 - ylsulfonyl)phenyl]butoxy}hexyl)amino]ethyl} phenol;
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexy!]oxy}butyl)-N-(l -methyl- l-phenylethyl)benzenesulfonamide;
5-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]- ethyl}amino)hexyl]oxy}butyl)-2-methoxybenzenesulfonamide; 3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}butyl)-5-pentylbenzenesulfonamide;
(E)-2-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}butyl)phenyl]-N-methylethenesulfonamide; 2-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]ethanesulfonamide;
5-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)[l,l'-biphenyl]-3-sulfonamide;
3-Fluoro-5-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;
5-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)-3-trifluoromethylbenzenesulfonamide ;
3.(4- { [6-( { (2R)-2-Hydroxy-2-[4-hydroxy-3 -
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)-5-methylbenzenesulfonamide acetate ; N-{[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]sulfonyl} glycine;
Ν2- { [3 -(4- { [6-( { (2R)-2-Hydroxy-2-[4-hydroxy-3 -
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]sulfonyl}glycinamide;
and salts, solvates, and physiologically functional derivatives thereof.
Particularly preferred compounds of the invention include:
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy } butyl)benzenesulfonamide;
3-(4-{[6-({(2S)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}butyl)benzenesulfonamide;
3-(4-{[6-({(2R/S)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}butyl)benzenesulfonamide; 3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)heptyl]oxy}propyl)benzenesulfonamide;
3-(3-{[7-({(2S)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)heptyl]oxy}propyl)benzenesulfonamide;
3-(3-{[7-({(2R/S)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)heptyl]oxy}propyl)benzenesulfonamide;
and salts, solvates, and physiologically functional derivatives thereof.
Of these compounds, 3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)- phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide and 3-(3-{[7-({(2R)-2-hydroxy-2-[4- hydroxy-3-hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamide are especially preferred. In the definition of R1 where 'R6 and R7 together with the nitrogen atom to which they are bonded, form a 5-, 6-, or 7- membered nitrogen containing ring', the term "5-, 6-, or 7- membered nitrogen containing ring" means a 5-, 6-, or 7- membered saturated or unsaturated ring which includes the sulfonamide nitrogen atom and optionally 1 or 2 other heteroatoms independently selected from nitrogen, sulphur, and oxygen. Suitable examples of such a ring include piperidinyl, morpholinyl, and piperazinyl.
In the definition of R1, specifically the optional substituents on R6 and R7, the term "5-, 6-, or 7- membered heterocyclic ring" means a 5-, 6-, or 7- membered fully or partially saturated or unsaturated ring which includes 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, sulphur, and oxygen. Suitable examples of such a ring include pyrrolyl, furyl, thienyl, pyridinyl, pyrazinyl, pyridazinyl, imidazolyl, tetrazolyl, tetrahydrofuranyl, oxazolyl, thiazolyl, thiadiazolyl, piperidinyl, morpholinyl, and piperazinyl.
In the definition of X, the term "alkenylene" includes both cis and trans structures. Suitable examples of alkenylene groups include -CH=CH-.
The compounds of formulae (I), (la) and (lb) include an asymmetric centre, namely the carbon atom of the
-CH- I OH group. The present invention includes both (S) and (R) enantiomers either in substantially pure form or admixed in any proportions.
Similarly, where R4 and R5 are different groups, the carbon atom to which they are attached is an asymmetric centre and the present invention includes both (S) and (R) enantiomers at this centre either in substantially pure form or admixed in any proportions.
Thus the compounds of formulae (I), (la) and (lb) include all enantiomers and diastereoisomers as well as mixtures thereof in any proportions.
Salts and solvates of compounds of formulae (I), (la) and (lb) which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable. However, salts and solvates having non-pharmaceutical ly acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formulae (I), (la) and (lb) and their pharmaceutically acceptable salts, solvates, and physiologically functional derivatives.
By the term "physiologically functional derivative" is meant a chemical derivative of a compound of formula (I), (la) or (lb) having the same physiological function as the parent compound of formula (I), (la) or (lb), for example, by being convertible in the body thereto. According to the present invention, examples of physiologically functional derivatives include esters.
Suitable salts according to the invention include those formed with both organic and inorganic acids or bases. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, triphenyl acetic, sulphamic, sulphanilic, succinic, oxalic, fumaric, maleic, malic, glutamic, aspartic, oxaloacetic, methanesulphonic, ethanesulphonic, arylsulphonic (for example p-toluenesulphonic, benzenesulphonic, naphthalenesulphonic or naphthalenedisulphonic), salicylic, glutaric, gluconic, tricarballylic, cinnamic, substituted cinnamic (for example, phenyl, methyl , methoxy or halo substituted cinnamic, including 4-methyl and 4-methoxycinnamic acid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic), naphthaleneacrylic (for example naphthalene-2-acrylic), benzoic, 4-methoxybenzoic, 2- or 4- hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, benzeneacrylic (for example 1,4- benzenediacrylic) and isethionic acids. Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases such as dicyclohexyl amine and N-methyl-D-glucamine.
Advantageously, preferred compounds of the invention such as 3-(4-{[6-({(2R)-2-hydroxy-2-[4- hydroxy-3-(hydroxymethyl)-phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide and 3- (3 - { [7-( {(2R)-2-hydroxy-2- [4-hydroxy-3 -hydroxymethyl)phenyl]ethyl } - amino)heptyl]oxy}propyl)benzenesulfonamide are provided in the form of a crystalline salt, for example selected from those exemplified in the experimental section below. Said crystalline salts have favourable physical properties such as low hygroscopicity and/or improved stability.
Particularly preferred salts include the cinnamate, 4-methoxycinnamate, 4-methylcinnamate, naphthalenepropenoate and 4-phenylcinnamate salts.
Pharmaceutically acceptable esters of the compounds of formulae (I), (la) and (lb) may have a hydroxyl group converted to a C^alkyl, aryl, aryl Cι.6 alkyl, or amino acid ester.
As mentioned above, the compounds of formulae (I), (la) and (lb) are selective β2- adrenoreceptor agonists as demonstrated using functional or reporter gene readout from cell lines transfected with human beta-adrenoreceptors as described below. Compounds according to the present invention also have the potential to combine long duration of effect with rapid onset of action. Furthermore, certain compounds have shown an improved therapeutic index in animal models relative to existing long-acting β2-agonist bronchodilators. As such, compounds of the invention may be suitable for once-daily administration.
Compounds of formulae (I), (la) and (lb) and their pharmaceutically acceptable salts, solvates, and physiologically functional derivatives have use in the prophylaxis and treatment of clinical conditions for which a selective β2-adrenoreceptor agonist is indicated. Such conditions include diseases associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary diseases (COPD) (e.g. chronic and wheezy bronchitis, emphysema), respiratory tract infection and upper respiratory tract disease (e.g. rhinitis, including seasonal and allergic rhinitis).
Other conditions which may be treated include premature labour, depression, congestive heart failure, skin diseases (e.g. inflammatory, allergic, psoriatic, and proliferative skin diseases), conditions where lowering peptic acidity is desirable (e.g. peptic and gastric ulceration) and muscle wasting disease.
Accordingly, the present invention provides a method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which a selective β2-adrenoreceptor agonist is indicated, which comprises administration of a therapeutically effective amount of a compound of formula (I), (la) or (lb), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof. In particular, the present invention provides such a method for the prophylaxis or treatment of a disease associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease. In a further aspect the present invention provides such a method for the prophylaxis or treatment of a clinical condition selected from premature labour, depression, congestive heart failure, skin diseases (e.g. inflammatory, allergic, psoriatic, and proliferative skin diseases), conditions where lowering peptic acidity is desirable (e.g. peptic and gastric ulceration) or muscle wasting disease.
In the alternative, there is also provided a compound of formula (I), (la) or (lb) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for use in medical therapy, particularly, for use in the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which a selective β2-adrenoreceptor agonist is indicated. In particular, there is provided a compound of formula (I), (la) or (lb) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for the prophylaxis or treatment of a disease associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease. In a further aspect, there is provided a compound of formula (I), (la) or (lb) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for the prophylaxis or treatment of a clinical condition selected from premature labour, depression, congestive heart failure, skin diseases (e.g. inflammatory, allergic, psoriatic, and proliferative skin diseases), conditions where lowering peptic acidity is desirable (e.g. peptic and gastric ulceration) or muscle wasting disease.
The present invention also provides the use of a compound of formula (I), (la) or (lb), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which a selective β2-adrenoreceptor agonist is indicated, for example a disease associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease. In a further aspect, there is provided a compound of formula (I), (la) or (lb), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition selected from premature labour, depression, congestive heart failure, skin diseases (e.g. inflammatory, allergic, psoriatic, and proliferative skin diseases), conditions where lowering peptic acidity is desirable (e.g. peptic and gastric ulceration) and muscle wasting disease.
The amount of a compound of formula (I), (la) or (lb), or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, and the particular disorder or disease being treated. The compounds of the invention may be administered by inhalation at a dose of from 0.0005mg to 10 mg, preferably 0.005mg to 0.5mg. The dose range for adult humans is generally from 0.0005 mg to lOOmg per day and preferably 0.01 mg to lmg per day.
While it is possible for the compound of formula (I), (la) or (lb), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof to be administered alone, it is preferable to present it as a pharmaceutical formulation.
Accordingly, the present invention further provides a pharmaceutical formulation comprising a compound of formula (I), (la) or (lb) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients.
Hereinafter, the term "active ingredient" means a compound of formula (I), (la) or (lb), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), inhalation (including fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulisers or insufflators), rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine, or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator. Formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier substance) such as lactose or starch. Use of lactose is preferred. Each capsule or cartridge may generally contain between 20μg-10mg of the compound of formula (I) optionally in combination with another therapeutically active ingredient. Alternatively, the compound of the invention may be presented without excipients. Packaging of the formulation may be suitable for unit dose or multi-dose delivery. In the case of multi-dose delivery, the formulation can be pre- metered (eg as in Diskus, see GB 2242134 or Diskhaler, see GB 2178965, 2129691 and 2169265) or metered in use (eg as in Turbuhaler, see EP 69715). An example of a unit-dose device is Rotahaler (see GB 2064336). The Diskus inhalation device comprises an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet hermetically but peelably sealed thereto to define a plurality of containers, each container having therein an inhalable formulation containing a compound of formula (I) preferably combined with lactose. Preferably, the strip is sufficiently flexible to be wound into a roll. The lid sheet and base sheet will preferably have leading end portions which are not sealed to one another and at least one of the said leading end portions is constructed to be attached to a winding means. Also, preferably the hermetic seal between the base and lid sheets extends over their whole width. The lid sheet may preferably be peeled from the base sheet in a longitudinal direction from a first end of the said base sheet. Spray compositions for topical delivery to the lung by inhalation may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant. Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain the compound of formula (I) optionally in combination with another therapeutically active ingredient and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, especially 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. Carbon dioxide or other suitable gas may also be used as propellant. The aerosol composition may be excipient free or may optionally contain additional formulation excipients well known in the art such as surfactants eg oleic acid or lecithin and cosolvents eg ethanol. Pressurised formulations will generally be retained in a canister (eg an aluminium canister) closed with a valve (eg a metering valve) and fitted into an actuator provided with a mouthpiece.
Medicaments for administration by inhalation desirably have a controlled particle size. The optimum particle size for inhalation into the bronchial system is usually 1-1 Oμm, preferably 2- 5μm. Particles having a size above 20μm are generally too large when inhaled to reach the small airways. To achieve these particle sizes the particles of the active ingredient as produced may be size reduced by conventional means eg by micronisation. The desired fraction may be separated out by air classification or sieving. Preferably, the particles will be crystalline. When an excipient such as lactose is employed, generally, the particle size of the excipient will be much greater than the inhaled medicament within the present invention. When the excipient is lactose it will typically be present as milled lactose, wherein not more than 85% of lactose particles will have a MMD of 60-90μm and not less than 15% will have a MMD of less than 15μm.
Intranasal sprays may be formulated with aqueous or non-aqueous vehicles with the addition of agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants.
Solutions for inhalation by nebulation may be formulated with an aqueous vehicle with the addition of agents such as acid or alkali, buffer salts, isotonicity adjusting agents or antimicrobials. They may be sterilised by filtration or heating in an autoclave, or presented as a non-sterile product.
Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose an acacia. Preferred unit dosage formulations are those containing an effective dose, as hereinbefore recited, or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
The compounds and pharmaceutical formulations according to the invention may be used in combination with or include one or more other therapeutic agents, for example selected from anti-inflammatory agents, anticholinergic agents (particularly an M|, M2, Mι/M2 or M3 receptor antagonist), other β2-adrenoreceptor agonists, antiinfective agents (e.g. antibiotics, antivirals), or antihistamines. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with one or more other therapeutically active agents, for example selected from an anti-inflammatory agent (for example a corticosteroid or an NSAID), an anticholinergic agent, another β2-adrenoreceptor agonist, an antiinfective agent (e.g. an antibiotic or an antiviral), or an antihistamine. Preferred are combinations comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a corticosteroid, and/or an anticholinergic, and/or a
PDE-4 inhibitor. Preferred combinations are those comprising one or two other therapeutic agents.
It will be clear to a person skilled in the art that, where appropriate, the other therapeutic ingredient(s) may be used in the form of salts, (e.g. as alkali metal or amine salts or as acid addition salts), or prodrugs, or as esters (e.g. lower alkyl esters), or as solvates (e.g. hydrates) to optimise the activity and/or stability and/or physical characteristics (e.g. solubility) of the therapeutic ingredient. It will be clear also that where appropriate, the therapeutic ingredients may be used in optically pure form.
Suitable anti-inflammatory agents include corticosteroids and NSAIDs. Suitable corticosteroids which may be used in combination with the compounds of the invention are those oral and inhaled corticosteroids and their pro-drugs which have anti-inflammatory activity. Examples include methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6α,9α- difluoro-17α-[(2-furanylcarbonyl)oxy]-l 1 β-hydroxy-16α-methyl-3-oxo-androsta-l,4-diene-l 7β- carbothioic acid S-fluoromethyl ester, 6α,9α-difluoro-l l β-hydroxy-16α-methyl-3-oxo-17α- propionyloxy- androsta-l,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl) ester, beclomethasone esters (e.g. the 17-propionate ester or the 17,21-dipropionate ester), budesonide, flunisolide, mometasone esters (e.g. the furoate ester), triamcinolone acetonide, rofleponide, ciclesonide, butixocort propionate, RPR- 106541, and ST- 126. Preferred corticosteroids include fluticasone propionate, 6α,9α-difluoro-l lβ-hydroxy-16α-methyl-17α-[(4-methyl-l,3-thiazole-5- carbonyl)oxy]-3-oxo-androsta-l,4-diene-17β-carbothioic acid S-fluoromethyl ester and 6α,9α- difluoro- 17α-[(2-furanylcarbonyl)oxy]- 1 1 β-hydroxy- 16α-methyl-3-oxo-androsta- 1 ,4-diene- 17β- carbothioic acid S-fluoromethyl ester, more preferably 6α,9α-difluoro-17α-[(2- furanylcarbonyl)oxy]- 1 1 β-hydroxy-16α-methyl-3-oxo-androsta- 1 ,4-diene- 17β-carbothioic acid S-fluoromethyl ester.
Suitable NSAIDs include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g. adenosine 2a agonists), cytokine antagonists (e.g. chemokine antagonists) or inhibitors of cytokine synthesis. Suitable other β2-adrenoreceptor agonists include salmeterol (e.g. as the xinafoate), salbutamol
(e.g. as the sulphate or the free base), formoterol (e.g. as the fumarate), fenoterol or terbutaline and salts thereof.
Of particular interest is use of the compound of formula (I) in combination with a phosphodiesterase 4 (PDE4) inhibitor or a mixed PDE3/PDE4 inhibitor. The PDE4-specific inhibitor useful in this aspect of the invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family as well as PDE4. Generally it is preferred to use a PDE4 inhibitor which has an IC50 ratio of about 0.1 or greater as regards the IC50 for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity. For the purposes of this disclosure, the cAMP catalytic site which binds R and S rolipram with a low affinity is denominated the "low affinity" binding site (LPDE 4) and the other form of this catalytic site which binds rolipram with a high affinity is denominated the "high affinity" binding site (HPDE 4). This term "HPDE4" should not be confused with the term "hPDE4" which is used to denote human PDE4.
Initial experiments may be conducted to establish and validate a [3H]-rolipram binding assay. Details of this work are given in the Binding Assays described in detail below.
Phosphodiesterase and Rolipram Binding Assays
Assay method 1A
Isolated human monocyte PDE4 and hrPDE (human recombinant PDE4) was determined to exist primarily in the low affinity form. Hence, the activity of test compounds against the low affinity form of PDE4 can be assessed using standard assays for PDE4 catalytic activity employing 1 μM
[3H]cAMP as a substrate (Torphv et al.. J. of Biol. Chem., Vol. 267, No. 3 ppl798-1804, 1992). Rat brain high speed supernatants were used as a source of protein and both enantiomers of [-1H]- rolipram were prepared to a specific activity of 25.6 Ci/mmol. Standard assay conditions were modified from the published procedure to be identical to the PDE assay conditions, except for the last of the cAMP: 50mM Tris HCI (pH 7.5), 5 mM MgCl2, 50 μM 5'-AMP and 1 nM of
[3H]-roliρram (Torphy eLaf, J. of Biol. Chem., Vol. 267, No. 3 pp 1798- 1804, 1992). The assay was run for 1 hour at 30° C. The reaction was terminated and bound ligand was separated from free ligand using a Brandel cell harvester. Competition for the high affinity binding site was assessed under conditions that were identical to those used for measuring low affinity PDE activity, expect that [3H]-cAMP was not present.
Assay method IB Measurement of Phosphodiesterase Activity
PDE activity was assayed using a [3H]cAMP SPA or [3H]cGMP SPA enzyme assay as described by the supplier (Amersham Life Sciences). The reactions were conducted in 96-well plates at room temperature, in 0.1 ml of reaction buffer containing (final concentrations): 50 M Tris-HCI, pH 7.5, 8.3 mM MgCl2, 1.7 mM EGTA, [3H]cAMP or [3H] cGMP (approximately 2000 dpm/pmol), enzyme and various concentrations of the inhibitors. The assay was allowed to proceed for 1 hr and was terminated by adding 50 μl of SPA yttrium silicate beads in the presence of zinc sulfate. The plates were shaken and allowed to stand at room temperature for 20 min. Radiolabeled product formation was assessed by scintillation spectrometry.
r3H1R-rolipram binding assay
The [3H]R-rolipram binding assay was performed by modification of the method of Schneider and co-workers, see Nicholson, et al.. Trends Pharmacol. Sci., Vol. 12, pp.19-27 (1991) and McHale et al.. Mol. Pharmacol., Vol. 39, 109-113 (1991). R-Rolipram binds to the catalytic site of PDE4 see Torphy et al-, Mol. Pharmacol., Vol. 39, pp. 376-384 (1991). Consequently, competition for [3H]R-rolipram binding provides an independent confirmation of the PDE4 inhibitor potencies of unlabeled competitors. The assay was performed at 30°C for 1 hr in 0.5 μl buffer containing (final concentrations): 50 mM Tris-HCI, pH 7.5, 5 mM MgCI2, 0.05% bovine serum albumin, 2 nM [3H]R-rolipram (5.7 x 104 dpm/pmol) and various concentrations of non- radiolabeled inhibitors. The reaction was stopped by the addition of 2.5 ml of ice-cold reaction buffer (without [3H]-R-rolipram) and rapid vacuum filtration (Brandel Cell Harvester) through Whatman GF/B filters that had been soaked in 0.3% polyethylenimine. The filters were washed with an additional 7.5 ml of cold buffer, dried, and counted via liquid scintillation spectrometry. The preferred PDE4 inhibitors of use in this invention will be those compounds which have a salutary therapeutic ratio, i.e., compounds which preferentially inhibit cAMP catalytic activity where the enzyme is in the form that binds rolipram with a low affinity, thereby reducing the side effects which apparently are linked to inhibiting the form which binds rolipram with a high affinity. Another way to state this is that the preferred compounds will have an IC50 ratio of about 0.1 or greater as regards the IC5Q for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity.
A further refinement of this standard is that of one wherein the PDE4 inhibitor has an IC50 ratio of about 0.1 or greater; said ratio is the ratio of the IC5Q value for competing with the binding of InM of [3H]R-rolipram to a form of PDE4 which binds rolipram with a high affinity over the IC50 value for inhibiting the PDE4 catalytic activity of a form which binds rolipram with a low affinity using 1 μM[3H]-cAMP as the substrate.
Examples of useful PDE4 inhibitors are: (R)-(+)-l-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone; (R)-(+)-l-(4-bromobenzyl)-4-[(3-cyclopentyIoxy)-4-methoxyphenyl]-2-pyrrolidone; 3-(cyclopentyloxy-4-methoxyphenyl)-l-(4-N'-[N2-cyano-S-methyl-isothioureido]benzyl)-2- pyrrolidone; cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-carboxylic acid]; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l-ol]; (R)-(+)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; and (S)-(-)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate.
Most preferred are those PDE4 inhibitors which have an IC50 ratio of greater than 0.5, and particularly those compounds having a ratio of greater than 1.0. Preferred compounds are cis 4- cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-carboxylic acid, 2-carbomethoxy-4- cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l-one and c _-[4-cyano- 4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l-ol]; these are examples of compounds which bind preferentially to the low affinity binding site and which have an IC50 ratio of 0.1 or greater.
Other compounds of interest include:
Compounds set out in U.S. patent 5,552,438 issued 03 September, 1996; this patent and the compounds it discloses are incorporated herein in full by reference. The compound of particular interest, which is disclosed in U.S. patent 5,552,438, is c/'_'-4-cyano-4-[3-(cyclopentyloxy)-4- methoxyphenyl]cyclohexane-l-carboxylic acid (also known as cilomalast) and its salts, esters, pro-drugs or physical forms;
AWD- 12-281 from Asta Medica (Hofgen, N. et al- 15th EFMC Int Symp Med Chem (Sept 6-10,
Edinburgh) 1998, Abst P.98; CAS reference No. 247584020-9); a 9-benzyladenine derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plough; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD- 168787) and attributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakko in W099/16766; K-34 from Kyowa Hakko; V-l 1294 A from Napp (Landells, L.J. etal. Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23,
Geneva) 1998] 1998, 12 (Suppl. 28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and a pthalazinone (WO99/47505, the disclosure of which is hereby incorporated by reference) from Byk-Gulden; Pumafentrine, (-)-p-[(4_/R*,106S*)-9-ethoxy- 1,2,3, 4,4a, 10b-hexahydro-8- methoxy-2-methylbenzo[c][l,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide which is a mixed PDE3/PDE4 inhibitor which has been prepared and published on by Byk-Gulden, now Altana; arofylline under development by Almirall-Prodesfarma; VM554/UM565 from Vemalis; or T-440 (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther,1998, 284(1): 162), and T2585.
Other possible PDE-4 and mixed PDE3/PDE4 inhibitors include those listed in WOO 1/13953, the disclosure of which is hereby incorporated by reference.
Suitable anticholinergic agents are those compounds that act as antagonists at the muscarinic receptor, in particular those compounds which are antagonists of the Mi and M receptors. Exemplary compounds include the alkaloids of the belladonna plants as illustrated by the likes of atropine, scopolamine, homatropine, hyoscyamine; these compounds are normally administered as a salt, being tertiary amines. These drugs, particularly the salt forms, are readily available from a number of commercial sources or can be made or prepared from literature data via, to wit: Atropine - CAS-51-55-8 or CAS-51-48-1 (anhydrous form), atropine sulfate - CAS-5908-99-6; atropine oxide - CAS-4438-22-6 or its HCI salt - CAS-4574-60-1 and methylatropine nitrate - CAS-52-88-0.
Homatropine - CAS-87-00-3, hydrobromide salt - CAS-51-56-9, methylbromide salt - CAS-80- 49-9. Hyoscyamine (d, I) - CAS-101-31-5, hydrobromide salt - CAS-306-03-6 and sulfate salt - CAS-
6835-16-1.
Scopolamine - CAS-51-34-3, hydrobromide salt - CAS-6533-68-2, methylbromide salt- CAS- 155-41-9. Preferred anticholinergics include ipratropium (e.g. as the bromide), sold under the name Atrovent, oxitropium (e.g. as the bromide) and tiotropium (e.g. as the bromide) (CAS-139404-
48-1). Also of interest are: methantheline (CAS-53-46-3), propantheline bromide (CAS- 50-34- 9), anisotropine methyl bromide or Valpin 50 (CAS- 80-50-2), clidinium bromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul), isopropamide iodide (CAS-71-81-8), mepenzolate bromide (U.S. patent 2,918,408), tridihexethyl chloride (Pathilone, CAS-4310-35-4), and hexocyclium methylsulfate (Tral, CAS-1 15-63-9). See also cyclopentolate hydrochloride (CAS-
5870-29-1), tropicamide (CAS-1508-75-4), trihexyphenidyl hydrochloride (CAS-144-1 1-6), pirenzepine (CAS-29868-97-1), telenzepine (CAS-80880-90-9), AF-DX 116, or methoctramine, and the compounds disclosed in WOO 1/04118, the disclosure of which is hereby incorporated by reference.
Suitable antihistamines (also referred to as Hi-receptor antagonists) include any one or more of the numerous antagonists known which inhibit H receptors, and are safe for human use. All are reversible, competitive inhibitors of the interaction of histamine with Hpreceptors. The majority of these inhibitors, mostly first generation antagonists, have a core structure, which can be represented by the following formula:
Figure imgf000017_0001
This generalized structure represents three types of antihistamines generally available: ethanolamines, ethylenediamines, and alkylamines. In addition, other first generation antihistamines include those which can be characterized as based on piperizine and phenothiazines. Second generation antagonists, which are non-sedating, have a similar structure-activity relationship in that they retain the core ethylene group (the alkylamines) or mimic the tertiary amine group with piperizine or piperidine. Exemplary antagonists are as follows: Ethanolamines: carbinoxamine maleate, clemastine fumarate, diphenylhydramine hydrochloride, and dimenhydrinate.
Ethylenediamines: pyrilamine amleate, tripelennamine HCI, and tripelennamine citrate. Alkylamines: chlropheniramine and its salts such as the maleate salt, and acrivastine. Piperazines: hydroxyzine HCI, hydroxyzine pamoate, cyclizine HCI, cyclizine lactate, meclizine HCI, and cetirizine HCI.
Piperidines: Astemizole, levocabastine HCI, loratadine or its descarboethoxy analogue, and terfenadine and fexofenadine hydrochloride or another pharmaceutically acceptable salt. Azelastine hydrochloride is yet another H] receptor antagonist which may be used in combination with a PDE4 inhibitor.
Examples of preferred anti-histamines include methapyrilene and loratadine.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a corticosteroid.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an antihistamine.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor and a corticosteroid.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic and a PDE-4 inhibitor.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a physiologically acceptable diluent or carrier represent a further aspect of the invention. The individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.
According to a further aspect of the invention, there is provided a process for preparing a compound of formula (I), (la) or (lb) or a salt, solvate, or physiologically functional derivative thereof which comprises a process (a) (b) (c) or (d) as defined below followed by the following steps in any order:
(i) optional removal of any protecting groups; (ii) optional separation of an enantiomer from a mixture of enantiomers;
(iii) optional conversion of the product to a corresponding salt, solvate, or physiologically functional derivative thereof.
In one general process (a), a compound of formula (I), (la) or (lb) may be obtained by deprotection of a protected intermediate, for example of formula (II):
Figure imgf000019_0001
or a salt or solvate thereof, wherein R1, R2, R3, R4, R5, m, and n are as defined for the compound of formula (I), (la) or (lb), R8, R9, and R10 are each independently either hydrogen or a protecting group provided that at least one of R8, R9, and R10 is a protecting group, and R14 is either hydrogen or a protecting group.
Suitable protecting groups may be any conventional protecting group such as those described in
"Protective Groups in Organic Synthesis" by Theodora W Greene and Peter G M Wuts, 3rd edition (John Wiley & Sons, 1999). Examples of suitable hydroxyl protecting groups represented by R8 and R9 are esters such as acetate ester, aralkyl groups such as benzyl, diphenylmethyl, or triphenylmethyl, and tetrahydropyranyl. Examples of suitable amino protecting groups represented by R'° include benzyl, α-methylbenzyl, diphenylmethyl, triphenylmethyl, benzyloxycarbonyl, tert-butoxycarbonyl, and acyl groups such as trichloroacetyl or trifluoroacetyl.
As will be appreciated by the person skilled in the art, use of such protecting groups may include orthogonal protection of groups in the compounds of formula (II) to facilitate the selective removal of one group in the presence of another, thus enabling selective functionalisation of a single amino or hydroxyl function. For example, the -CH(OH) group may be orthogonally protected as -CHOR14 using, for example, a trialkylsilyl group such as triethylsilyl. A person skilled in the art will also appreciate other orthogonal protection strategies, available by conventional means as described in Theodora W Greene (see above).
The deprotection to yield a compound of formula (I), (la) or (lb) may be effected using conventional techniques. Thus, for example, when R8, R9, and/or R10 is an aralkyl group, this may be cleaved by hydrogenolysis in the presence of a metal catalyst (e.g. palladium on charcoal).
When R8 and/or R9 is tetrahydropyranyl this may be cleaved by hydrolysis under acidic conditions. Acyl groups represented by R10 may be removed by hydrolysis, for example with a base such as sodium hydroxide, or a group such as trichloroethoxycarbonyl may be removed by reduction with, for example, zinc and acetic acid. Other deprotection methods may be found in Theodora W Greene (see above). In a particular embodiment of process (a), R8 and R9 may together represent a protecting group as in the compound of formula (III).
Figure imgf000020_0001
or a salt or solvate thereof, wherein R1, R2, R3, R4, R5, R14, m, and n are as defined for the compound of formula (I) , (la) or (lb), R11 and R12 are independently selected from hydrogen, . 6alkyl, or aryl. In a preferred aspect, both R11 and R12 are methyl.
A compound of formula (III) may be converted to a compound of formula (I), (la) or (lb) by hydrolysis with dilute aqueous acid, for example acetic acid or hydrochloric acid in a suitable solvent or by transketalisation in an alcohol, for example ethanol, in the presence of a catalyst such as an acid (for example, toluenesulphonic acid) or a salt (such as pyridinium tosylate) at normal or elevated temperature.
It will be appreciated that the protecting groups R8, R9, R10 and R14 (including the cyclised protecting group formed by R8 and R9 as depicted in formula (III) may be removed in a single step or sequentially. The precise order in which protecting groups are removed will in part depend upon the nature of said groups and will be readily apparent to the skilled worker. Preferably, when R8 and R9 together form a protecting group as in formula (III) this protecting group is removed together with any protecting group on the CH(OH) moiety, followed by removal of R10.
Compounds of formulae (II) and (III) wherein R10 is hydrogen may be prepared from the corresponding compound of formula (IV):
Figure imgf000021_0001
or a salt or solvate thereof, wherein R1, R2, R3, R4, R5, R8, R9 m, and n are as defined for the compound of formula (II) or (III).
The conversion of a compound of formula (IV) to a compound of formula (II) or (III) may be effected by treatment with a base, for example a non-aqueous base, such as potassium trimethylsilanoate, or an aqueous base such as aqueous sodium hydroxide, in a suitable solvent such as tetrahydrofuran.
Compounds of formula (IV) may be prepared from the corresponding compound of formula (V):
_ (CH2 2)',m -0— (CH2)n — C ≡ CH (V)
Figure imgf000021_0002
or a salt or solvate thereof, wherein R4, R5, R8, R9, m and n are as defined for the compound of formula (IV); by coupling with a compound of formula (VI):
Figure imgf000021_0003
wherein R1, R2, and R3 are as defined for the compound of formula (IV) and L is a leaving group, such as a halo group (typically, bromo or iodo) or a sulphonate ester such as a haloalkyl sulphonate (typically, trifluoromethanesulphonate), followed by reduction.
The coupling of compound of formula (V) with a compound of formula (VI) is conveniently effected in the presence of a catalyst system such as bis (triphenylphosphine) palladium dichloride with an organic base such as a trialkylamine, for example, triethylamine, in a suitable solvent, for example acetonitrile or dimethylformamide. The resulting alkyne may then be reduced, either with or without being isolated to form the compound of formula (IV). The reduction may be effected by any suitable method such as hydrogenation in the presence of a catalyst, for example, palladium/charcoal or platinum oxide.
Alternatively, in the compounds of formula (VI) R1, R2, and R3 may represent groups convertible into R1, R2, and R3, for example halo groups. This is particularly useful where one of the groups R1, R2, and R3 may be affected by any of the subsequent transformations. Thus, for example, where R1 contains an alkenylene moiety, this is preferably introduced after the reduction of the alkyne formed by reaction of compounds (V) and (VI).
Compounds of formula (VI) are commercially available or may be prepared by methods well known to the person skilled in the art.
Compounds of formula (V) may be prepared by coupling a compound of formula (VII):
Figure imgf000022_0001
or a salt or solvate thereof, wherein R8 and R9 are as defined for the compound of formula (V) with a compound of formula (VIII):
L1CR4R5(CH2)m — O— (CH2)n — C ≡ CH (VIII)
wherein R , R , m and n are as defined for the compound of formula (V) and L1 is a leaving group, for example a halo group (typically bromo or iodo) or a sulphonate such as an alkyl sulphonate (typically, methanesulphonate), an arylsulphonate (typically, toluenesulphonate), or a haloalkyl sulphonate (typically, trifluoromethanesulphonate).
The coupling of a compound of formula (VII) with a compound of formula (VIII) may be effected in the presence of a base, such as a metal hydride, for example sodium hydride, or an inorganic base such as cesium carbonate, in an aprotic solvent, for example dimethylformamide.
Compounds of formula (VIII) may be prepared from the corresponding dihaloalkane and hydroxyalkyne by conventional chemistry, typically in the presence of an inorganic base, such as aqueous sodium hydroxide, under phase transfer conditions in the presence of a salt such as tetraalkylammonium bromide.
Compounds of formula (VII) may be prepared by ring closure of a compound of formula (IX):
Figure imgf000023_0001
wherein R8 and R9 are as defined for the compound of formula (VII) and R13 is
Figure imgf000023_0002
for example tert-butyl, or aryl, for example phenyl. The ring closure may be effected by treatment with a base, such as a metal hydride, for example sodium hydride, in the presence of an aprotic solvent, for example, dimethylformamide.
Compounds of formula (IX) may be prepared from the corresponding ketone of formula (X):
Figure imgf000023_0003
wherein R8 and R9 and R13 are as defined for the compound of formula (IX), by reduction by any suitable method, for example by treatment with borane, in the presence of a chiral catalyst, such as CBS-oxazaborolidine, in a suitable solvent such as tetrahydrofuran.
The compound of formula (X) may be prepared from the corresponding halide of formula (XI)
Figure imgf000023_0004
wherein R8 and R9 are as defined for the compound of formula (X) and Y is halo, suitably bromo.
The conversion of a compound of formula (XI) to a compound of formula (X) may be effected by reaction with the protected amine HN(COOR13)2 wherein R13 is as defined for the compound of formula (X) in the presence of an inorganic base such as cesium carbonate, followed by selective removal of one of the COOR13 groups, for example by treatment with an acid such as trifluoroacetic acid.
Compounds of formula (XI) may be prepared from the corresponding compound having free hydroxymethyl and hydroxy substituents (which itself may be prepared from 2-bromo- 1 -(4- hydroxy)-3-hydroxymethyl-phenethyl)ethanone, the preparation of which is described in GB2140800, by treatment with 2-methoxypropane in acetone in the presence of an acid e.g. p- toluene-sulphonic acid in a nitrogen atmosphere or by other standard methods) by forming the protected groups R8OCH2- and R90- wherein R8 and R9 are as defined for the compound of formula (XI). Such methods are described in DE 3513885 (Glaxo).
Compounds of formula (II) or (III) wherein R10 is a protecting group may be prepared as described in process (b) below, or by analogous methods to process (c) below.
In a further process (b), a compound of formula (I) , (la) or (lb) may be obtained by alkylation of an amine of formula (XII):
Figure imgf000024_0001
wherein R8, R9, R10 and R14 are each independently either hydrogen or a protecting group. Suitable protecting groups are discussed in the definition of compounds of formula (II);
with a compound of formula (XIII):
Figure imgf000024_0002
wherein R1, R2, R3, R4, R5, m, and n are as defined for the compound of formula (I), (la) or (lb) and L2 is a leaving group such as halo (typically bromo); followed by removal of any protecting groups present by conventional methods as described above for the deprotection of compounds of formula (II).
The reaction of compounds of formulae (XII) and (XIII) is optionally effected in the presence of an organic base such as a trialkylamine, for example, diisopropylethylamine, and in a suitable solvent for example dimethyl formamide.
Compounds of formula (XII) are known in the art (for example EP-A 0947498) or may be readily prepared by a person skilled in the art. Compounds of formula (XIII) may be prepared by coupling a compound of formula (VI) as defined above, or a precursor thereof (wherein one or more of the substituents R1, R2 or R3 is a group which is convertible to the desired group R1, R2, or R3) with a compound of formula (VIII) as shown above wherein R4, R5, m, and n are as defined for the compound of formula (XIII) and L1 is a leaving group as defined above.
The coupling of a compound of formula (VIII) with a compound (VI) may be effected by methods analogous to those described above for coupling a compound of formula (V) with a compound of formula (VI), followed by reduction of the resulting alkyne of formula (XIV):
Figure imgf000025_0001
also as described above. If necessary, the substituents R , R , and/or R3 may be formed by conventional conversions where a precursor is present.
An alkyne of formula (XIV) may also be prepared by reacting a compound of formula (XV):
L2CR4R5(CH2)m L3 (XV)
with a compound of formula (XVI ):
Figure imgf000025_0002
using conventional methods, for example as described for the preparation of compounds (VIII).
Compounds of formula (XVI ) may be prepared by reacting a hydroxyalkyne
XX with a compound of formula (VI) using methods analogous to those described above for coupling a compound (V) with a compound (VI). In a further process (c) a compound of formula (I), (la) or (lb) may be prepared by reacting a compound of formula (XVII):
Figure imgf000026_0001
wherein R8, R9 and R14 are as hereinbefore defined and L is a leaving group, is reacted with an amine of formula (XVIII):
(XVIII)
Figure imgf000026_0002
followed by removal of any protecting groups present by conventional methods as described above for the deprotection of compounds of formula (II).
The reaction may be effected using conventional conditions for such displacement reactions.
Compounds of formula (XVII) may be prepared by methods known in the art.
Compounds of formula (XVIII) may be prepared by reacting a compound of formula (XIII) with an amine RI0NH2.
In a further process (d) a compound of formula (I), (la) or (lb) may be prepared by removal of a chiral auxiliary from a compound of formula (Ha):
Figure imgf000026_0003
wherein R1 - R5, R8, R9, m and n are as hereinbefore defined and R15 represents a chiral auxiliary. A "chiral auxiliary" is a moiety that is introduced into a molecule to influence the stereochemistry of the product formed, and is removed in whole or part at a later time. A chiral auxiliary may simultaneously function as a protecting group.
Many chiral auxiliaries are commercially available, and persons skilled in the art would choose one based on the properties desired i.e. the absolute stereochemistry desired and compatibility with the processes being used. Chiral auxiliaries suitable for use in this process include but are not limited to the S-isomer and/or the R-isomer of phenyl glycinol and substituted derivatives thereof.
The chiral auxiliary is preferably a moiety of the formula:
Figure imgf000027_0001
or a single enantiomer thereof, wherein R16 represents C^alkyl or optionally substituted phenyl or benzyl wherein the optional substitution is one or more independently selected from
Figure imgf000027_0002
halogen, hydroxy,
Figure imgf000027_0003
or nitro e.g. para-hydroxyphenyl.
More preferably the chiral auxiliary is a moiety:
Figure imgf000027_0004
wherein R16 is as defined above. Alternatively it may be a moiety of formula:
Figure imgf000027_0005
wherein R16 is as defined above.
Preferably R16 represents phenyl optionally substituted as described above, Most preferably R represents unsubstituted phenyl.
The chiral auxiliary in this process may typically be removed by hydrogenolysis using for example a palladium on carbon catalyst or preferably using palladium hydroxide (Pearlman's catalyst). Advantageously when Pearlman's catalyst is used the removal of the chiral auxiliary is most efficient. This method of removal is especially suitable where R1 is phenyl or a substituted phenyl. Alternatively the nitrogen, to which the auxiliary is attached, may be derivatised under oxidising conditions to form the N-oxide before elimination by heating to give a secondary amine. A compound of formula (Ila) may be prepared by reduction of the corresponding alkyne of formula (XIX):
Figure imgf000028_0001
Preferably in the compounds of formulae (Ila) and (XIX) the protecting groups R8 and R9 together form a group -CRnR12- as in the compounds of formula (III).
Reduction of an alkyne of formula (XIX) may be effected by methods well known in the art, for example by catalytic hydrogenation, using palladium on charcoal or more preferably palladium hydroxide (Pearlman's catalyst). The chiral auxiliary may also be removed under reductive conditions. Advantageously, therefore the reduction of the alkyne and removal of the chiral auxiliary may be effected concomitantly in a 'one-pot' reaction.
An alkyne of formula (XIX) may be prepared by reaction of a compound of formula (XX)
Figure imgf000028_0002
(XX) with a compound of formula (VI) under conditions described above for coupling of compounds
(V) and (VI).
A compound of formula (XX) may be prepared by reacting a compound of formula (Xlla):
Figure imgf000028_0003
with an aldehyde of formula (XXI): O
JL (CH2)mO(CH2)n = (χχ|)
using known methods for effecting reductive amination, e.g. sodium triacetoxyborohydride in a solvent such as chloroform
An aldehyde of formula (XXI) may be prepared from a corresponding halide of formula (VIII) using standard techniques such as treatment with sodium bicarbonate in a solvent such as DMSO at elevated temperature, preferably in the range 130-160°C.
A compound of formula (Xlla) may be prepared from a compound of formula (XXII):
Figure imgf000029_0001
Wherein R8, R9 and R15 are as hereinbefore defined by treatment with a reducing agent such as a hydride source e.g. sodium borohydride. Preferably this process takes place in the presence of an inert metal salt such as calcium chloride suitably at non-extreme temperatures e.g. below ambient, such as 0°C. This allows the desired stereochemistry to be introduced efficiently with good enantiomeric excess at an early stage in the synthesis, using inexpensive and relatively harmless reagents. Furthermore, the enantiomeric excess may be increased by recrystallisation of the product of this process.
A compound of formula (XXII) may be prepared from a compound of formula (XI) as hereinbefore defined by reaction with an appropriate chiral amine, e.g. (S)-phenylglycinol, in the presence of a non-nucleophilic base in an inert solvent at non-extreme temperatures.
A detailed description of a process analogous to Route (d) may be found in published International Application Number WO/0196278.
In the above process (d) it is preferred that the protecting groups R8 and R9 together form a protecting group as depicted in formula (III).
It will be appreciated that in any of the routes (a) to (d) described above, the precise order of the synthetic steps by which the various groups and moieties are introduced into the molecule may be varied. It will be within the skill of the practitioner in the art to ensure that groups or moieties introduced at one stage of the process will not be affected by subsequent transformations and reactions, and to select the order of synthetic steps accordingly. The enantiomeric compounds of the invention may be obtained (i) by separation of the components of the corresponding racemic mixture, for example, by means of a chiral chromatography column, enzymic resolution methods, or preparing and separating suitable diastereoisomers, or (ii) by direct synthesis from the appropriate chiral intermediates by the methods described above.
Optional conversions of a compound of formula (I), (la) or (lb) to a corresponding salt may conveniently be effected by reaction with the appropriate acid or base. Optional conversion of a compound of formula (I), (la) or (lb) to a corresponding solvate or physiologically functional derivative may be effected by methods known to those skilled in the art.
According to a further aspect, the present invention provides novel intermediates for the preparation of compounds of formula (I), (la) or (lb), for example: compounds of formula (II) and (III) as defined above, or an optical isomer, a salt, or a protected derivative thereof; particularly, a compound selected from:
3- {4-[(6- { [(2R)-2-(2,2-Dimethyl-4H- 1 ,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide; 4-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-l ,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;
2- {4-[(6- { [(2R)-2-(2,2-Dimethyl-4H- 1 ,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;
3 - {4-[(6- { [(2R)-2-(2,2-Dimethyl-4H- 1 ,3 -benzodioxin-6-y l)-2- hydroxyethyl]amino}hexyl)oxy]butyl}-N-methylbenzenesulfonamide;
(lR)-l-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-[(6-{4-[3-(morpholin-4- ylsulfonyl)phenyl]butoxy}hexyl)amino]ethanol;
3- {4-[(6- { [(2R)-2-(2,2-Dimethyl-4H- 1 ,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}-N,N-dimethylbenzenesulfonamide; 3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}-N-isopropylbenzenesulfonamide;
N-(tert-Butyl)-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide; and
(1 R)-l-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-[(6-{4-[3-( piperidin-1 - ylsulfonyl)phenyl]butoxy}hexyl)amino]ethanol;
( 1 R)- 1 -(2,2-Dimethyl-4H- 1 ,3 -benzodioxin-6-yl)-2-[(6- {4-[3-(piperazin- 1 - ylsulfonyl)phenyl]butoxy}hexyl)amino]ethanol;
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-hydroxyethyl]- amino} hexyl)oxy]butyl} -N-( 1 -methyl- 1 -phenylethyl)benzenesulfonamide; N-[4-(Aminosulfonyl)phenyl]-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;
{3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4-H-l,3-benzodioxin-6-yl)-2- hydroxyethyl]- amino}hexyl)oxy]butyl}phenyl}methanesulfonamide; 5. {4-[(6- { [(2R)-2-(2,2-Dimethyl-4H- 1 ,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}-2-methoxybenzenesulfonamide;
3-{5-[(5-{[(2R)-2-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-hydroxyethyl] - amino}pentyl)oxy]pentyl}benzenesulfonamide; 3-{3-[(7-{[(2R)-2-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-hydroxyethyl] - amino}heptyl)oxy]propyl}benzenesulfonamide;
3-[6-(4-{[(2R)-2-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-hydroxyethyl]- amino}butoxy)hexyl]benzenesulfonamide;
3-{3-[(6-{[(2R)-2-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]propyl}benzenesulfonamide;
3-{4-[(5-{[(2R)-2-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}pentyl)oxy]butyl}benzenesulfonamide;
N-[3-(Aminosulfonyl)phenyl]-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide; N-Benzyl-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;
3-{4-[(6-{[2-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2- hydroxyethyl]amino } hexy l)oxy]butyl } benzenesulfonamide;
3-{4-[(6-{[(2S)-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;
N-(4- { [(3- {4-[(6- { [(2R)-2-(2,2-Dimethyl-4H- 1 ,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)sulfonyl]amino}phenyl)acetamide;
N-Cyclobutyl-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)-2- hydroxyethyl] amino } hexy l)oxy]butyl } benzenesulfonamide; N-Cyclohexyl-3- {4-[(6- { [(2R)-2-(2,2-dimethyl-4H- 1 ,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}-N-(4-fluorophenyl)benzenesulfonamide;
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}- hexyl)oxy]butyl}-N-(2-morpholin-4-ylethyl)benzenesulfonamide;
(E)-2-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-l ,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)-N-methylethenesulfonamide;
(E)-2-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)ethenesulfonamide; 5-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}[l,l'-biphenyl]-3-sulfonamide;
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}-5-pentylbenzenesulfonamide;
compounds of formula (IV) as defined above, or an optical isomer, a salt, or a protected derivative thereof; particularly, a compound selected from: 3_[4_({6-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)butyl]benzenesulfonamide;
N-[4-(Aminosulfonyl)phenyl]-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo- l,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide; 3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)butyl]-N-(4-fluorophenyl)benzenesulfonamide;
3.[4_({6-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)butyl]-N-(2-morpholin-4-ylethyl)benzenesulfonamide;
N-Cyclohexyl-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-l ,3-benzodioxin-6-yl)-2-oxo-l ,3-oxazolidin- 3-yl]hexyl}oxy)butyl]benzenesulfonamide;
4-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l ,3-oxazolidin-3- yl]hexyl}oxy)butyl]benzenesulfonamide;
2-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-l ,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)butyl]benzenesulfonamide; (5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-3-(6-{4-[3-(piperazin-l- ylsulfonyl)phenyl]butoxy}hexyl)-l,3-oxazolidin-2-one;
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)butyl]-N-(l -methyl- l-phenylethyl)benzenesulfonamide;
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l ,3-oxazolidin-3- yl]hexyl}oxy)butyl]-N-methylbenzenesulfonamide;
(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-3-(6-{4-[3-(morpholin-4- ylsulfonyl)phenyl]butoxy}hexyl)-l,3-oxazolidin-2-one;
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)butyl]-N,N-dimethylbenzenesulfonamide; 3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)butyl]-N-isopropylbenzenesulfonamide;
N-(tert-Butyl)-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-
3-yl]hexyl}oxy)butyl]benzenesulfonamide;
(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-3-(6-{4-[3-(piperidin-l - ylsulfonyl)phenyl]butoxy}hexyl)-l,3-oxazolidin-2-one;
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)butyl]phenylmethanesulfonamide;
3-[5-({5-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]pentyl}oxy)pentyl]benzenesulfonamide; 5-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-l ,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)butyl]-2-methoxybenzenesulfonamide;
3-[3-({7-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]heptyl}oxy)propyl]benzenesulfonamide;
3-(6-{4-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]butoxy}hexyl)benzenesulfonamide;
4-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)butyl]phenyl}butane-l-sulfonamide; 3-[5-({6-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)pentyl]benzenesulfonamide;
3-[6-({6-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)hexyl]benzenesulfonamide; 3-[3-({6-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yljhexyl } oxy)propyl] benzenesu lfonamide;
3-[4-({5-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]pentyl}oxy)butyl]benzenesulfonamide;
N-[3-(Aminosulfonyl)phenyl]-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo- 1 ,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide;
N-Benzyl-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)butyl]benzenesulfonamide;
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)butyl]-N-[(ethylamino)carbonyl]benzenesulfonamide; 3-[4-({6-[5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)butyl]benzenesulfonamide;
N-{4-[({3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl } oxy)butyl]phenyl } sulfonyl)amino]phenyl } acetamide;
N-Cyclobutyl-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)butyl]benzenesulfonamide;
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)butyl]-N-[2-(2-hydroxyethoxy)ethyl]benzenesulfonamide;
(E)-2-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)butyl]phenyl}-N-methylethenesulfonamide; (E)-2-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl } oxy)butyl]phenyl } ethenesulfonamide;
3-[((tert-Butoxycarbonyl){[2-(trimethylsilyl)ethoxy]methyl}amino)sulfonyl]-5-[4-({6-[(5R)-5-
(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3-yl]hexyl}oxy)butyl]-l,l'- biphenyl; tert-Butyl {3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)butyl]-5-pentylphenyl}sulfonyl{[2-(trimethylsilyl)ethoxy]methyl}carbamate; l-{4-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl} oxy)butyl] phenyl } methanesulfonamide; and l-{2-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-l ,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)butyl]phenyl}methanesulfonamide.
For a better understanding of the invention, the following Examples are given by way of illustration.
SYNTHETIC EXAMPLES
Throughout the examples, the following abbreviations are used: LC: Liquid Chromatography
LCMS: Liquid Chromatography Mass Spectrometry.
RT : retention time
THF : tetrahydofuran DMF : N,N-dimethylformamide bp : boiling point ca : circa h : hour(s) min : minute(s) XRPD : X-ray powder diffraction
All temperatures are given in degrees centigrade.
Silica gel refers to Merck silica gel 60 Art number 7734.
Flash silica gel refers to Merck silica gel 60 Art number 9385.
Biotage refers to prepacked silica gel cartridges containing KP-Sil run on flash 12i chromatography module.
Bond Elut are prepacked cartridges used in parallel purifications, normally under vacuum. These are commercially available from Varian.
LC was conducted on a Luna C 18(2) column (5cm x 2.0mm ID) eluting with 0.05%v/v trifluoroacetic acid in water (solvent A) and 0.05%v/v trifluoroacetic acid in acetonitrile (solvent
B) using the following elution gradient 0.00-8.00 min 0%B, 8.00-8.01 min 95%B, 8.01-10.00 min 0%B at a flow rate of 1.0ml/ min with a column temperature of 40°C.
NMR experiments at 400MHz (unless specified otherwise).
LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4.6 mm ID) eluting with 0.1% HC02H and 0.01 M ammonium acetate in water (solvent A), and 0.05% HC02H 5% water in acetonitrile (solvent B), using the following elution gradient 0-0.7 min 0%B, 0.1-4.2 min 100%B, 4.2-5.3 min 0%B, 5.3-5.5 min 0%B at a flow rate of 3 ml/min. The mass spectra were recorded on a Fisons VG Platform spectrometer using electrospray positive and negative mode (ES+ve and ES-ve).
The XRPD analysis shown in the Figures were performed on a Phillips X'pert Pro powder diffractometer, Model PW3040/60, serial number DY1379. The method runs from 2 to 45 degrees 2Theta with 0.02 degree 2Theta step size and a 2 second collection time at each step.
Example 1: 3-(4-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyl]ethyl>amino)- hexyl]oxy}butyl)benzenesulfonamide acetate i) Di(tert-butyl) 2-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate Cesium carbonate (70.4g) was added to a stirred suspension of 2-bromo-l-(2,2-dimethyl-4H-l,3- benzodioxin-6-yl)ethanone, (Glaxo, DE 3513885, 1985) (61.8g) and di-t-butyl iminodicarboxylate (47.15g) in acetonitrile (600ml) under nitrogen. After vigorous stirring at 21° for 24 h the mixture was diluted with water (cα800ml) and the product was extracted with diethyl ether (1 litre, then 200ml). The combined organic layers were washed with brine, dried (MgS0 ) and concentrated to c 400ml. The white crystals were collected by filtration, washed with diethyl ether and dried to give the title compound (24.4g) δ (CDC13) 7.78(1H, dd, J 8, 2Hz), 7.65 (1H, brs), 6.87(1H, d, J 8Hz), 4.97(2H, s), 4.88(2H, s), 1.56(6H, s) and 1.48 (18H, s) . Further concentration of the mother liquors gave additional product (13.8g). A third crop (7.1g) was obtained by chromatographing the mother liquors on silica gel, evaporating the appropriate eluate and triturating with diethyl ether.
ii) tert-Butyl 2-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxoethylcarbamate Trifluoroacetic acid (92ml) was added to a stirred solution of di(tert-butyl) 2-(2,2-dimethyl-4H- l,3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate, (352.55g) in dichloromethane (3.61itres) at 21° and the reaction was stirred for 1.5 h. Aqueous NaOH solution (1.75 litres) was added and after 10 min the phases were separated. The organic layer was washed with water, dried (MgS04) and evaporated to an oil. This was stored under high vacuum overnight and then triturated with hexane:ether (3: 1) to give the crude product (226.61g). This was purified by recrystallisation from diethyl ether to give the title compound (122.78g). Further product (61.5 g) was obtained from the mother liquors by evaporation and chromatography on a Biotage using 15% ethyl acetate in hexane. LCMS RT = 3.37min.
iii) tert-Butyl (2R)-2-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl>2-hydroxyethylcarbamate
A 2M solution of borane - dimethyl sulphide in THF (28ml) was added slowly to a IM solution of (R)-tetrahydro-l-methyl-3,3-diphenyl-lH,3H-pyrrolo[l,2-c][l ,3,2]oxazaborole in toluene (56ml) at 0° under nitrogen. A solution of tert-butyl 2-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)- 2-oxoethylcarbamate, (108.2g) in THF (1.3 litres) was added slowly keeping the temperature below 5° followed by 2M solution of borane - dimethyl sulphide in THF (252ml) over 50 min.
After 1 h, 2M HCI (170ml) was added with cooling and the mixture was partitioned between ethyl acetate and water . The organic layer was washed with saturated NaHC03 solution and brine and dried (MgS04). The solution was concentrated and the product purified by chromatography on flash silica gel (800g), eluting successively with hexane:ethyl acetate (4: 1 then 3: 1) to give the title compound (93.3 g), LCMS RT = 3.31min.
iv) (5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-1.3-oxazolidin-2-one tert-Butyl (2R)-2-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate, (86.37g) in DMF (600ml) was added dropwise to a stirred suspension of sodium hydride (60% oil dispersion, 1 1.9g) in DMF (160ml) with cooling such that the internal temperature remained at
0° under nitrogen. The mixture was stirred at 21° for 2 h. The mixture was recooled to 0° and 2M HCI (134ml) was added. The mixture was diluted with water and the product was extracted with ethyl acetate twice. The solution was washed with brine twice, dried (MgS04) and evaporated to give the title compound (63.55 g) LCMS RT = 2.66min.
v) 6-Bromohexyl but-3-vnyl ether
3-Butyn-l-ol (42.4ml) was stirred vigorously with 1,6-dibromohexane (260ml) and tetrabutylammonium bisulphate (2.4g) in 50% aqueous sodium hydroxide solution (200ml) under nitrogen for 3 days. Water (ca 700ml) was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane (2 x 100ml) and the combined organic layers were washed with water, dried (MgS04) and concentrated. The residue in petroleum ether (bp 40 - 60°) was loaded onto a column of silica gel (1.5kg) and the column was eluted with petroleum ether (bp 40 - 60°), then 10% diethyl ether in petroleum ether (bp 40 - 60°) to give the title compound (103.3g), δ (CDC13) 3.56(2H, t, J 7Hz), 3.47(2H, t, J 7Hz), 3.42(2H, t, J 7Hz), 2.45(2H, m), 1.99(1H, t, J 2Hz), 1.87(2H, m), 1.60(2H, m) and 1.50 to 1.33 (4H, m).
vi) (5R)-3-.6-(But-3-vnyloxy)hexyl]-5-(2.2-dimethyl-4H-l,3-benzodioxin-6-yl)-l,3-oxazolidin- 2-one
(5R)-5-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)-l,3-oxazolidin-2-one (lOg) in DMF (100ml) was added dropwise to a stirred suspension of sodium hydride (60% oil dispersion, 2.33g) in DMF (50ml) with stirring under nitrogen and maintaining the internal temperature at 0°. Stirring was continued at 0 - 5° for 1 h. The mixture was recooled to 0° and a solution of 6-bromohexyl but-3-ynyl ether (14.7g) in DMF (50ml) was added over 1 min. The mixture was then stirred at
20 - 30° for 2 h. 2M HCI (9ml) was added and the mixture was partitioned between water and diethyl ether. The aqueous layer was extracted with more diethyl ether and the combined organic layers were washed twice with brine. After drying (MgS0 ) the solution was concentrated and loaded onto a column of silica gel (600g) set up in diethyl ether: petroleum ether (bp 40 - 60°) (1 :2). The column was eluted successively with this mixture, then (1 : 1) and then diethyl ether to give the title compound (13.88g) LCMS RT = 3.45min.
vii) 3-f4-((6-r(5RV5-("2.2-Dimethyl-4H-1.3-benzodioxin-6-vn-2-oxo-1.3-oxazolidin-3- yl]hexyl)oxy)but-l-ynyl]benzenesulfonamide (5R)-3-[6-(But-3-ynyloxy)hexyl]-5-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)-l,3-oxazolidin-2- one (1.79g) was stirred with 3-iodobenzene sulphonamide (1.4g) in acetonitrile:triethylamine
(1:1, 42ml) under nitrogen for 10 min. Cuprous iodide (0.083g) and dichlorobis(triphenylphosphine)palladium (0.192g) were added and the mixture was stirred for
17 h under nitrogen at 21°. The mixture was evaporated to dryness and the residue was chromatographed on silica gel (250g) in 30% ethyl acetate: petroleum ether (bp 40 - 60°), then
50%, then 75% and finally ethyl acetate to give the title compound (2.35g), LCMS RT =
3.44min.
viii) 3-r4-((6-r(5RV5-α.2-Dimethyl-4H-1.3-benzodioxin-6-vn-2-oxo-1.3-oxazolidin-3- yl1hexyUoxy)butyl]benzenesulfonamide
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)but-l-ynyl]benzenesulfonamide (2.35g) was stirred with platinum oxide (0.3g) in THF (30ml) under hydrogen for 2 h. The catalyst was removed by filtration using a filter aid and the filter cake was leached with ethyl acetate. The combined filtrates were passed through silica gel (200g) in ethyl acetate and the eluate was evaporated to give the title compound (2.32g),
LCMS RT = 3.49min. ix. 3-(4-r(6-(I(2RV2-('2.2-Dimethyl-4H-1.3-benzodioxin-6-yl .-2- hvdroxyethyl]amino}hexyl .oxy1butyl , benzenesulfonamide 3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)butyl]benzenesulfonamide (0.43g) was stirred in THF (10ml) while purging with a vigorous stream of nitrogen for 5 min. Potassium trimethylsilanoate (0.43g) was added and the mixture was stirred at 70° under nitrogen for 2.5 h. The mixture was partitioned between dichloromethane and pH 6.4 phosphate buffer and the aqueous layer was extracted with more dichloromethane. The combined organic layers were washed with water, dried (MgS04) and concentrated. The residue was purified on silica gel (60g), eluting successively with ethyl acetate : petroleum ether (bp 40 - 60°) (1: 1), ethyl acetate, 10% then 20% methanol in ethyl acetate to give the title compound (0.286g), LCMS RT = 2.56min.
x. 3-(4- . r6-({(2RV2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl]ethy amino)hexyl]oxy}butyl)benzenesulfonamide acetate 3-{4- (6- . r(2RV2-(2.2-dimethyl-4H- 1.3 -benzodioxin-6-vn-2- hydroxyethyl]amino}hexyOoxy]butv benzenesulfonamide (0.283g) was stirred with acetic acid (8ml") and water (4mD at 70° for 35 min before evaporating to dryness. The residue was re- evaporated twice with toluene to give the title compound (0.318g) LCMS RT = 2.34min. ES +ve 495 (MH.+.
Example 2: 4-(4- . r6-((('2RV2-Hvdroxy-2-r4-hvdroxy-3-
(hydroxymethyl)phenyl]ethy amino)hexyl]oxy}butyl)benzenesulfonamide acetate i . 4-.4-f .6-r( R■-5-f2.2-Dimethyl-4H-1.3-benzodioxin-6-yl ■-2-oxo-1.3-oxazolidin-3- yl]hexyl , oxy,but-l-ynyl]benzenesulfonamide was prepared using methods similar to those described in Example 1 vii.
LCMS RT = 3.47min.
ii') 4-r4-((6-r(5R')-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexy oxy)butyl]benzenesulfonamide was prepared using methods similar to those described in Example 1 viii. LCMS RT = 3.47min.
iiiH-(4-r(6-(r(2RV2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-vn-2- hydroxyethy 1] amino . hexy Doxy] butyl , benzenesu lfonamide was prepared using methods similar to those described in Example 1 ix. LCMS RT = 2.65min.
iv. 4-(4-{.6-(f(2RV2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyllethv amino)hexyl]oxylbutyl)benzenesulfonamide acetate was prepared using methods similar to those described in Example 1 x. LCMS RT = 2.38min, ES +ve 495 (MH)+.
Example 3: 2-(4- , ,6-( . (2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenvnethvUamino)hexyl]oxylbutyl)benzenesulfonamide acetate i') 2-r4-. (6-r(,5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yllhexyl > oxy.but- 1 -ynyll benzenesulfonamide was prepared using methods similar to those described in Example 1 vii. LCMS RT = 3.58min.
in 2-r4-({6-rr5RV5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-vn-2-oxo-1.3-oxazolidin-3- yl]hexyUoxy)butyl]benzenesulfonamide was prepared using methods similar to those described in Example 1 viii.
LCMS RT = 3.61min.
iii . 2- .4-.f6- . rf 2RV2-(2.2-Dimethyl-4H- 1.3 -benzodioxin-6-ylV2- hydroxyethyllaminolhexyDoxylbuty benzenesulfonamide was prepared using methods similar to those described in Example 1 ix.
LCMS RT = 2.80min.
iv. 2-f4- . r6-( .(2RV2-Hvdroxy-2-.4-hvdroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy) butyl, benzenesulfonamide acetate was prepared using methods similar to those described in Example 1 x. LCMS RT = 2.43 min, ES +ve 495 (MH)+.
Example 4: 3-(4-(r6-({("2RV2-Hvdroxy-2-r4-hvdroxy-3-('hvdroxymethyl)phenyl1ethvU- amino)hexyl]oxy . butvD-N-methylbenzenesulfonamide acetate i_ 3-r4-(l6-r(5RV5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl.-2-oxo-1.3-oxazolidin-3- yl]hexyl > oxy)but- 1 -ynyll-N-methylbenzenesulfonamide was prepared using methods similar to those described in Example 1 vii.
ES+ve 571 (MH)+.
ii) 3-r4-((6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexyUoxy)butyl1-N-methylbenzenesulfonamide was prepared using methods similar to those described in Example 1 viii.
ES+ve 575 (MH)+.
iii . 3- ( 4-IT6- .1 ( 2R ,-2-f 2.2-Dimethyl-4H- 1.3-benzodioxin-6-ylV2- hydroxyethyl]aminolhexyl .oxy]buty -N-methylbenzenesulfonamide was prepared using methods similar to those described in Example 1 ix.
ES+ve 549 (MH)+.
iv) 3-.4-(r6-(((2RV2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethvU- amino)hexyl]oxy}butyl)-N-methylbenzenesulfonamide acetate was prepared using methods similar to those described in Example 1 x.
LCMS RT = 2.45 min ES+ve 509 (MH)+. Example S: 2-(Hvdroxymethyl)-4-{(lR)-l-hydroxy-2-r_6- .4-r3-(morpholin-4- ylsulfonyOphenvUbutoxylhexyOaminolethvU phenol acetate iU5RV5- .2-Dimethyl-4H-1.3-benzodioxin-6-vn-3-r6-f (4-r3-(morpholin-4- ylsulfonyπphenyl1but-3-vnyl>oxy)hexyl]-1.3-oxazolidin-2-one was prepared using methods similar to those described in Example 1 vii.
ES+ve 627 (MH)+.
iiU5RV5-f2.2-Dimethyl-4H-1.3-benzodioxin-6-ylV3-('6-(4-r3-fmorpholin-4- ylsu lfonyl)phenyl]butoxy } hexyl )- 1.3 -oxazolidin-2-one was prepared using methods similar to those described in Example 1 viii.
ES+ve 631 (MH)+.
iiiUlRVl-('2.2-Dimethyl-4H-1.3-benzodioxin-6-yn-2-[(6-(4-r3-(morpholin-4- ylsulfonvDphenvπbutoxy}hexyl.amino]ethanol was prepared using methods similar to those described in Example 1 ix.
ES+ve 605 (MH)+.
iv) 2-(Hydroxymethvn-4- (( 1 R ,- 1 -hydroxy-2-|Y6- [4- [3 -(morpholin-4- ylsulfonyl,phenyl]butoxylhexyl)amino1ethyl)phenol acetate was prepared using methods similar to those described in Example lx.
LCMS RT = 2.54 min ES+ve 565 (MH)+.
Example 6: 3-(4-{r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hydroxymethyl)phenyl]ethyl. - amino)hexyl]oxylbutyl)-N.N-dimethylbenzenesulfonamide acetate i) 3-r4-((6-r("5RV5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-vn-2-oxo-1.3-oxazolidin-3- yl]hexyl}oxy,but-l-ynyl]-N,N-dimethylbenzenesulfonamide
A mixture of (5R)-3-[6-(but-3-ynyloxy)hexyl]-5-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)-l,3- oxazolidin-2-one (0.256g) and 3-bromo-N,N-dimethylbenzene sulphonamide (0.208g) in pyrrolidine (4ml) was degassed using vacuum/nitrogen cycle. Cuprous iodide (0.005g) and dichlorobis(triphenylphosphine)palladium (0.037g) were added and the mixture was stirred at
80° for 45 min under nitrogen. The mixture was diluted with EtOAc and washed with water. The aqueous phase was extracted with EtOAc and the combined organic phases washed with brine, dried (Na S04) and evaporated to dryness. The residue was dissolved in CH2C12 and applied to a silica Bond Elut Cartridge (lOg). The cartridge was eluted with CH2C12, cyclohexane/Et20, Et20 and EtOAc. Evaporation of the ether fractions gave an oil which was repurified by silica Bond Elut to give the title compound
Figure imgf000039_0001
585 (MH)+.
ii . 3-r4- 6-rr5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl"|hexyl . oxy)butyl]-N,N-dimethylbenzenesulfonamide was prepared using methods similar to those described in Example 1 viii.
ES+ve 587 (MH)+. iii . 3-(4-r(6-(r("2RV2-('2.2-Dimethyl-4H-1.3-benzodioxin-6-vn-2- hvdroxyethyllamino>hexyl .oxy1butv -N.N-dimethylbenzenesulfonamide was prepared using methods similar to those described in Example 1 ix. ES+ve 563 (MH)+.
iv. 3-.4-{r6- r2RV2-Hvdroxy-2-r4-hvdroxy-3-("hvdroxymethvnphenyllethyl)- amino)hexyl]oxy . butyl )-N.N-dimethylbenzenesulfonamide acetate was prepared using methods similar to those described in Example 1 x. LCMS RT = 2.52 min ES+ve 523 (MH)+.
Example 7: 3-(4-{r6-({(2RV2-Hvdroxy-2-r4-hvdroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy)butyl)-N-isopropylbenzenesulfonamide acetate i . 3-r4-. {6-l('5R')-5-f2.2-Dimethyl-4H-1.3-benzodioxin-6-ylV2-oxo-1.3-oxazolidin-3- yl]hexyl , oxy,but-l-ynyl]-N-isopropylbenzenesulfonamide was prepared using methods similar to those described in Example 6 i.
ES+ve 599 (MH)+.
ii') 3-[4-({6-[(5RV5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexyl . oxy)butyn-N-isopropylbenzenesulfonamide was prepared using methods similar to those described in Example 1 viii.
ES+ve 603 (MH)+.
iii) 3-(4-r(6-(r(2RV2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-vn-2- hvdroxyethyl]amino)hexyl)oxy]butyl . -N-isopropylbenzenesulfonamide was prepared using methods similar to those described in Example 1 ix.
ES+ve 577 (MH)+.
i v) 3 -(4- ( \6-( {(2R)-2-Hydroxy-2-[4-hydroxy-3 -("hvdroxymethyl)phenyl]ethyl } - amino)hexyl]oxy}butyl)-N-isopropylbenzenesulfonamide acetate was prepared using methods similar to those described in Example 1 x.
LCMS RT = 2.56 min ES+ve 537 (MH)+.
Example 8: N-,tert-Butyl.-3-.4- . r6-f .f2R)-2-hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl]ethy amino)hexyl]oxylbutyl)benzenesulfonamide acetate i . N-('teιt-Butvn-3-r4- 6-rf5RV5-('2.2-dimethyl-4H-1.3-benzodioxin-6-vn-2-oxo-1.3- oxazolidin-3-yl]hexyl , oxy)but-l-vnyl]benzenesulfonamide was prepared using methods similar to those described in Example 6i. ES+ve 613 (MH)+.
ii) N-(tert-Butvn-3-r4-. (6-r(5RV5-r2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3- oxazolidin-3-yl]hexyl . oxy)butyl]benzenesulfonamide was prepared using methods similar to those described in Example 1 viii. ES+ve 617 (MH)+. iii . N-('tert-Butvn-3-M-r(6-{r(2R)-2-(2.2-dimethyl-4H-1.3-benzodioxin-6-ylV2- hvdroxyethyl1amino}hexyl)oxy]butyl . benzenesulfonamide was prepared using methods similar to those described in Example 1 ix. ES+ve 591 (MH)+.
iv. N-(teit-Butyl)-3-(4-{r6-({(2R')-2-hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyl]ethy amino)hexyl1oxy}butyl)benzenesulfonamide acetate was prepared using methods similar to those described in Example lx. LCMS RT = 2.63 min ES+ve 551 (MH)+.
Example 9: 2-(Hvdroxymethyl)-4-{f lR')-l-hvdroxy-2-r(6-{4-[3-fpiperidin-l- ylsulfonyl)phenyl1butoxy}hexyl)amino]ethy phenol acetate i .5RV5-(,2.2-Dimethyl-4H-1.3-benzodioxin-6-vn-3-r6-('(4-r3-(' piperidin-l- ylsulfonyl)phenyribu.-3-ynyl . oxy,hexyl]-1.3-oxazolidin-2-one was prepared using methods similar to those described in Example 6 i. ES+ve 625 (MH)+.
ii . .5RV5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-vn-3-(6-(4-r3-(piperidin-l - ylsulfonvDphenyllbutoxy. hexyl)-l,3-oxazolidin-2-one was prepared using methods similar to those described in Example 1 viii. ES+ve 629 (MH)+.
iii) ( lRVl-(2.2-Dimethyl-4H-1.3-benzodioxin-6-vn-2-r('6-{4-r3-f piperidin-1 - ylsulfonyl)phenvπbutoxy}hexyl)amino]ethanol was prepared using methods similar to those described in Example 1 ix. ES+ve 603 (MH)+.
iv 2-(Hvdroxymethyl)-4-(πRVl -hvdroxy-2-[(6-(4-r3-(piperidin-l- ylsulfonyl)phenyl1butoxy)hexyl)amino]ethy phenol acetate was prepared using methods similar to those described in Example 1 x. LCMS RT = 2.72min ES+ve 563 (MH)+.
Example 10: l-.3-(4- ..6-( .(2R.-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl]ethy amino,-hexyl1oxy)butyl)phenyl]methanesulfonamide i , Sodium (3-iodophenyl)methanesulfonate
A solution of 3-iodobenzyl bromide (3g) and sodium sulphite (1.26g) in acetone (15ml) and water (30ml) was heated at 70° for 3h. The solvent was removed under reduced pressure and the residue was triturated in ether to give the title compound (3.8g ). LCMS RT=3.66 min.
ii) ( 3-Iodophenyl)methanesulfonyl chloride A stirred mixture of sodium (3-iodophenyl)methanesulfonate (3.6g ) and phosphoryl chloride (10ml ) in sulpholane (20ml) and acetonitrile (30ml ) was heated at 70° for 2h. The mixture was- poured onto crushed ice (200ml ) and the precipitated product was collected and dried to give the title product (2.8g) LCMS RT= 3.47 min. iii) ( -Iodophenyl .methanesulfonamide
A stirred solution of (3-iodophenyl)methanesulfonyl chloride (lg) in THF (20ml) was treated with 0.88 ammonia (25ml) at room temperature for 30 min. The solvent was removed under reduced pressure and the residue was triturated in ether to give the title compound (0.35g ). LCMS RT=2.71 min.
iv) {3-r4-({6-[(5R)-5-(2,2-Dimethyl-4H-1.3-benzodioxin-6-vn-2-oxo-1.3-oxazolidin3- yllhexyUoxy.but-l-vnyl] phenyl) methanesulfonamide was prepared using methods similar to those described in Example 1 vii. ES+ve 571 (MH)+
v) 3-r4-f(6-rf5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-vn-2-oxo-1.3-oxazolidin-3- yl]hexylloxy)butyl]phenylmethanesulfonamide was prepared using methods similar to those described in Example 1 viii.
ES+ve 575 (MH)+
vi) {3-{4-r(6-{r(2RV2-(2.2-Dimethyl-4-H-1.3-benzodioxin-6-yn-2- hvdroxyethyll amino}hexyl,oxy]buty pheny methanesulfonamide was prepared using methods similar to those described in Example 1 ix.
ES+ve 549 (MH)+
vii) r3-(4-{r6-( (2RV2-Hvdroxy-2-r4-hvdroxy-3-fhvdroxymethyl .phenyl1- ethvUamino)hexyl]oxy)butyl)phenyl]methanesulfonamide was prepared using methods similar to those described in Example 1 x.
LCMS RT=2.22 min ES+ve 509 (MH )+
Example 11: 3-, 5- . r5-({(2R)-2-Hydroxy-2-r4-hvdroxy-3-
(hydroxymethyl)phenyl]ethyUamino)pentyl]oxy)pentyl)benzenesulfonamide acetate i) 5-|Y5-Bromopentyl)oxy]pent-l -yne was prepared using methods similar to those described in Example 1 v. LCMS RT=3.62min.
ii) (5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-3-[5-(pent-4-ynyloxy)pentyl1-1.3-oxazolidin- 2-one was prepared using methods similar to those described in Example 1 vi. LCMS RT=3.50min.
iii) 3-r5-((5-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]pentv oxy)pent-l-vnyl1benzenesulfonamide was prepared using methods similar to those described in Example 1 vii. LCMS RT=3.42min.
iv) 3-r5-(,(5-r(5R)-5-(,2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]pentyl . oxy)pentyl1benzenesulfonamide was prepared using methods similar to those described in Example 1 viii. LCMS RT=3.58min.
v) 3-{5-l(5-(r(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroxyethyl]amino}pentyl)oxy1pentv benzenesulfonamide was prepared using methods similar to those described in Example 1 ix. LCMS RT=2.75min.
vi) 3-(5- . r5-α(2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyllethyl}amino)pentyl]oxy. pentyl)benzenesulfonamide acetate was prepared using methods similar to those described in Example 1 x. LCMS RT=2.46min, ES+ve 495 (MH)+.
Example 12: 3-(3-{.7-( .(2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl)phenyl1ethyl>amino)heptyl]oxy}propyl)benzenesulfonamide acetate i) 3- (7-Bromoheptyl)oxy]prop-l -yne was prepared using methods similar to those described in Example 1 v. LCMS RT=3.63min.
ii) .5R)-5-r2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-3-r7-rprop-2-vnyloxy)heptyll-1.3- oxazolidin-2-one was prepared using methods similar to those described in Example 1 vi. LCMS RT=3.57min.
iii) 3-r3-((7-r<'5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]heptyl}oxy)prop-l -vnyl]benzenesulfonamide was prepared using methods similar to those described in Example 1 vii. LCMS RT=3.51min.
iv) 3-r3-((7-r('5R)-5-r2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yllheptvUoxy)propyllbenzenesulfonamide was prepared using methods similar to those described in Example 1 viii. LCMS RT=3.58min.
v) 3 - .3 -IΪ7- .1.2R)-2-(2.2-Dimethyl-4H- 1.3 -benzodioxin-6-yl)-2- hvdroxyethyl]amino)heptyl)oxy1propyl}benzenesulfonamide was prepared using methods similar to those described in Example 1 ix. LCMS RT=2.75min. vi) 3-(3- . r7-( .(2R)-2-Hvdroxy-2-.4-hvdroxy-3-
(hydroxymethyl)phenvπethyl , amino)heptyl]oxyipropyl)benzenesulfonamide acetate was prepared using methods similar to those described in Example 1 x. LCMS RT=2.46min, ES+ve 495 (MH)+.
Example 13: 3- .6-r4-α.2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl)phenyllethvπamino)butoxy]hexyl. benzenesulfonamide acetate i) 6-(4-Bromobutoxy)hex- 1 -yne was prepared using methods similar to those described in Example 1 v.
LCMS RT=3.49min.
ii) (5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-3-r4-(hex-5-ynyloxy)butyl]-1.3-oxazolidin- 2-one was prepared using methods similar to those described in Example 1 vi.
LCMS RT=3.48min.
iii) 3-r6-(4-f(5R)-5-('2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yljbutoxy . hex - 1 -vnyDbenzenesulfonamide was prepared using methods similar to those described in Example 1 vii.
LCMS RT=3.42min.
iv) 3-.6-(4-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]butoxy)hexyl)benzenesulfonamide was prepared using methods similar to those described in Example 1 viii.
LCMS RT=3.58min.
v) 3-r6-(4- . r(2R)-2-r2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hydroxyethyl]amino)butoxy)hexyl]benzenesulfonamide was prepared using methods similar to those described in Example 1 ix.
LCMS RT=2.66min.
vi) 3- .6-r4-( .(2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hydroxymethyl)phenyl1ethyl)amino)butoxy]hexyl|benzenesulfonamide acetate was prepared using methods similar to those described in Example 1 x.
LCMS RT=2.47min, ES+ve 495 (MH)+.
Example 14: 4-.3-(4- . r6-(' ,('2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethvDphenyllethyl } amino .hexylloxy) butvDphenyl] butane- 1 -sulfonamide i) 4-(3-Iodophenyl)butyl methanesulfonate
4-(3-Iodophenyl)butan-l-ol (1.7g) was stirred with diisopropylamine (1.74ml) and methanesulfonyl chloride (0.66ml) in dichloromethane (50ml) at 21° for 2h. The solution was washed successively with sodium bicarbonate solution, water, water acidified with a few drops of 2M HCI and water, each time back extracting with dichloromethane. The combined organic layers were dried (MgS04) and evaporated to give the title compound (2.23 g), tic Rf =0.28 (1:3 ethyl acetate in cyclohexane)
ii) 4-(3-Iodophenyl)butane-l-sulfonamide
4-(3-Iodophenyl)butyl methanesulfonate (0.354g) was stirred with sodium iodide (0.75g) in acetone (5ml) under nitrogen for 3h and at 35° for 30min. The mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with more dichloromethane and the combined organic layers were washed with water. After drying (MgS0 ) the solution was evaporated to an oil. This was dissolved in ethanol (10ml) and water (5ml) and the mixture was refluxed on a steam bath for 12h with sodium sulfite (0.138g). The mixture was cooled and the solid was collected by filtration, washed with water and dried. This residue was refluxed with phosphorus oxychloride (4ml) under nitrogen for 4h and then blown dry with a stream of nitrogen. 0.880 Ammonia solution (5ml) was added and the mixture was refluxed for 2h. More ammonia solution (5ml) was added and refluxing was continued for 45min. The mixture was cooled and the solid was collected by filtration, washed with water and dried to give the title compound (0.2g) LCMS RT=3.15 min.
iii) 4-(3-r4- 6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexyl}oxy)but-l-ynyl]pheny butane-l-sulfonamide was prepared using methods similar to those described in Example 1 vii. LCMS RT=3.62min.
iv) 4-{3-[4-({6- (5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl1hexyl}oxy)butyl]phenyl . butane- 1-sulfonamide was prepared using methods similar to those described in Example 1 viii. LCMS RT=3.71min.
v) 4-r3-.4- . r6-( .f2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl1ethyl)amino)hexyl]oxy}butyl)phenyl]butane-l-sulfonamide
4-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- yl]hexyl}oxy)butyl]phenyl}butane-l-sulfonamide (0.097g) was stirred and refluxed with potassium trimethylsilanoate (O.lg) under nitrogen for 2h. The mixture was evaporated to dryness and re-evaporated with methanol. The residue was taken up in methanol and loaded onto a Bond Elut SCX2 cartridge (lOg) which had been preconditioned with methanol. The cartridge was left for 30min and then eluted successively with methanol and then 1% 0.880 aqueous ammonia solution in methanol. This gave the title compound (0.064g), LCMS RT=2.72min, ES+ve 551 (MH)+.
Example 15: 3-C5- . r6-q(2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyl1ethvUamino)hexyl]oxy|pentyl)benzenesulfonamide i) 5-r(6-bromohexyl)oxy]pent-l-vne was prepared using methods similar to those described in Example 1 v. GCMS RT = 5.6min
ii) (5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-3-[6-(pent-4-vnyloxy)hexyl]-1.3-oxazolidin- 2-one was prepared using methods similar to those described in Example 1 iv.
LCMS RT=3.65min
Hi) 3-rS-C 6-.f5R)-5 -f 2.2-Dimethyl-4H- 1.3 -benzodioxin-6-yl)-2-oxo- 1.3 -oxazol idin-3 - yl1hexyπoxy)pent-l-vnyl .benzenesulfonamide was prepared using methods similar to those described in Example 1 vii.
LCMS RT=3.76min
iv) 3-r5- 6-r.5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yllhexyUoxy)pentyl]benzenesulfonamide was prepared using methods similar to those described in Example 1 viii.
LCMS RT=3.57min
v) 3-.5-(r6-r{(2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyl]ethyl)amino)hexyl]oxy, pentyl)benzenesulfonamide was prepared using methods similar to those described in Example 14 v.
LCMS R=2.47min, ES+ve 509 (MH)+.
Example 16: 3-.6-(r6-( ,(2R)-2-Hvdroxy-2-.4-hydroxy-3- (hydroxymethyl)phenyl]ethyl>amino)hexyl]oxy}hexyl)benzenesulfonamide i) 6-[Y6-Bromohexyl)oxy "lhex- 1 -yne was prepared using methods similar to those described in Example 1 v. GCMS RT=5.99min
ii) (5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-3-[6-.hex-5-vnyloxy)hexyl]-l,3-oxazolidin- 2-one was prepared using methods similar to those described in Example 1 iv. LCMS RT=3.73min
iii) 3- 6-. (6-[(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl1hexyl}oxy)hex-l-ynvnbenzenesulfonamide was prepared using methods similar to those described in Example 1 vii. LCMS RT=3.74min
iv) 3-r6-r(6-r.5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexynoxy)hexyllbenzenesulfonamide was prepared using methods similar to those described in Example 1 viii. LCMS RT=3.69min v) 3-r6-(r6-(((2R)-2-hvdroxy-2-r4-hvdroχy-3-
,hvdroxymethyl)phenyl]ethyl , amino)hexyl1oxylhexyl)benzenesuIfonamide was prepared using methods similar to those described in Example 14 v. LCMS RT=2.57min, ES+ve 523 (MH)+.
Example 17: 3-(3- _ r6-( .(-2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyllethv amino)hexylloxy}propyl)benzenesulfonamide acetate i) 3-[(6-Bromohexyl)oxy]prop-l-yne was prepared using methods similar to those described in Example 1 v. δ (CDCI3) 4.13 (2H, s), 3.52 (2H, t, J 7Hz), 3.41 (2H, t, J 7Hz), 2.42 (I H, t J 2Hz), 1.91 to 1.82
(2H, m), 1.66 to 1.58 (2H, m) and 1.51 to 1.35 (4H, m).
ii) (5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-3-r6-(prop-2-vnyloxy)hexyl]-1.3-oxazolidin- 2-one was prepared using methods similar to those described in Example 1 vi.
LCMS RT=3.45min
iii) 3-r3-({6-[f5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexyl) oxy)prop- 1 -ynyl]benzenesulfonamide was prepared using methods similar to those described in Example 1 vii.
LCMS RT=3.52min
iv) 3-r3-f(6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexyUoxy)propyl]benzenesulfonamide was prepared using methods similar to those described in Example 1 viii.
LCMS RT=3.48min
v) 3-(3-rf6-(r(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hydroxyethyl1amino}hexyl)oxy]propyl} benzenesulfonamide was prepared using methods similar to those described in Example 1 ix.
LCMS RT=2.81 min
vi) 3-(3-{ 6-df2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy|propyl)benzenesulfonamide acetate was prepared using methods similar to those described in Example 1 x.
LCMS RT=2.48min, ES+ve 481 (MH)+.
Example 18: 3-.4- . r5-( . (2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyllethyl}amino)penrylloxy)butyl)benzenesulfonamide acetate i) 4-[(5-Bromopentyl)oxy]but- 1 -vne was prepared using methods similar to those described in Example 1 v. δ (MeOD) 3.43 (2H, t, J 7Hz), 3.41 to 3.32 (4H, m), 2.32 (2H, dt, J 2,7Hz), 2.15 (IH, t, J 2Hz),
1.81 to 1.73 (2H, m), 1.54 to 1.38 (4H, m). ii) (5R)-3- 5-fBut-3-vnyloxy)pentyl]-5-.2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-1.3-oxazolidin- 2-one was prepared using methods similar to those described in Example 1 vi. LCMS RT=3.87min
iii) 3-r4-f(5- (5R)-5-('2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]pentyl}oxy)but-l-ynvnbenzenesulfonamide was prepared using methods similar to those described in Example 1 vii. LCMS RT=3.47min
iv) 3-r4-((5-r(5R)-5-('2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]pentv oxy)butvHbenzenesulfonamide aas prepared using methods similar to those described in Example 1 viii. LCMS RT=3.37min
v) 3-(4-r(5-U(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hydroxyethyl]amino . pentyl)oxy1butyl , benzenesulfonamide was prepared using methods similar to those described in Example 1 ix. LCMS RT=2.81min vi) 3-(4-(r5-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)pentyl]oxy}butyl)benzenesulfonamide acetate was prepared using methods similar to those described in Example 1 x. LCMS RT=2.41 min, ES+ve 481 (MH)+.
Example 19: N-r3-(Aminosulfonyl)phenvn-3-(,4-(r6- (2R)-2-hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl]ethyl)amino)hexyl]oxy}butyl)benzenesulfonamide acetate N-r3-(Aminosulfonyl)phenyl1-3-r4-((6-r(5R)-5-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo- 1.3-oxazolidin-3-yl]hexyl)oxy)but-l -vnyl]benzenesulfonamide was prepared using methods similar to those described in Example 1 vii.
LCMS RT=3.72min.
i) N-r3-(Aminosulfonyl)phenyll-3-r4-. (6-f('5R)-5-f2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2- oxo-1.3-oxazolidin-3-yllhexy oxy)butyl]benzenesulfonamide was prepared using methods similar to those described in Example 1 viii.
LCMS RT=3.61min.
i i) N-r 3 -(Aminosulfonyl)phenyll-3 - (4- . ( 6- ( r(2R)-2-(2.2-dimethyl-4H- 1.3 -benzodioxin-6-yl)-2- hydroxyethyl]amino)hexyl)oxy]butyl>benzenesulfonamide was prepared using methods similar to those described in Example 1 ix.
LCMS RT=2.88min. iii) N-r3-(Aminosulfonyl)phenyll-3-.4-(r6-(' .('2R)-2-hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl)phenyl1ethv amino)hexyl]oxylbutyl)benzenesulfonamide acetate was prepared using methods similar to those described in Example 1 x. LCMS RT=2.95min, ES+ve 650 (MH)+.
Example 20: l-r4-(4-(r6-(((2R)-2-Hydroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl1ethyl}amino)hexyl]oxy}butyl)phenvnmethanesulfonamide i) Sodium (4-iodophenyl .methanesulfonate was prepared using methods similar to those described in Example 10 i. tic (Si02, 1 : 1 EtOAc/ Cyclohexane/ 1 % AcOH) Rf=0.57).
ii) l-,4-Iodophenyl)methanesulfonamide was prepared using methods similar to those described in Example 10 iii.
LCMS RT=2.63min
iii) l-(4-r4-((6-r.5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl1hexyl)oxy)but-l-ynyl]phenv methanesulfonamide was prepared using methods similar to those described in Example 1 vii.
LCMS RT=3.43min
iv) l-{4-r4-({6-I.5R)-5- .2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- y l]hexyl . oxy)butyl]phenyl ) methanesulfonamide was prepared using methods similar to those described in Example 1 viii.
LCMS RT=3.50min
v) 1 -, 4-(4- . \6-( i (2R)-2-Hvdroxy-2- r4-hvdroxy-3 -
(hydroxymethyl)phenyl]ethy amino)hexynoxy)butyl)phenyl]methanesulfonamide was prepared using methods similar to those described in Example 14 v. LCMS RT=2.35, ES +ve 509 (MH)+.
Example 21: l-r2-(4-{r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl)phenyl]ethyl}amino)hexyl1oxy)butyl)phenyl]methanesulfonamide i) Sodium (2-iodophenyl)methanesulfonate was prepared using methods similar to those described in Example 10 i. tic (Si02, 1 :1 EtOAc/Cyclohexane/ 1% AcOH) Rf=0.63.
ii) 1 -( 2-Iodophenyl)methanesulfonamide was prepared using methods similar to those described in Example 10 iii.
LCMS RT=2.44min
iii) l-(2-r4-(-(6-lf5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl1hexyl . oxy)but-l-vnyπphenyl. methanesulfonamide was prepared using methods similar to those described in Example 1 vii. LCMS RT=3.46min
iv) l-(2-r4-( .6-r.5R)-5-('2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- vnhexyl . oxy.butyHphenv methanesulfonamide was prepared using methods similar to those described in Example 1 viii.
LCMS RT=3.50min
v) 1 -r2-f 4- _ \6-( , , 2R)-2-Hvdroxy-2- r4-hvdroxy-3 -
(hvdroxymethyl)phenyl]ethyl)amino)hexyl1oxy}butyl)phenyl]methanesulfonamide was prepared using methods similar to those described in Example 14 v.
LCMS RT=2.40, ES+ve 509 (MH)+.
Example 22: N-Benzyl-3-(4- . r6-(, .(2R)-2-hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl)phenyl]ethvπamino)hexynoxy>butyl)benzenesulfonamide acetate i) N-Benzyl-3-r4-. {6-r(5R)-5-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yllhexyl ) oxy)but- 1 -ynyl] benzenesulfonamide was prepared using methods similar to those described in Example 6 i. ES+ve 647 (MH)+
ii) N-Benzyl-3-r4-((6-r(5R)-5-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexyl , oxy)butyl]benzenesulfonamide was prepared using methods similar to those described in Example 1 viii. ES+ve 651 (MH)+
iii) N-Benzyl-3- .4-.(6- . r(2R)-2-f2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2- hydroxyethyl]amino)hexyl)oxy1butyl . benzenesulfonamide was prepared using methods similar to those described in Example 1 ix. ES+ve 625 (MH)+
iv) N-benzyl-3 -(4- , \6-( . , 2R)-2-hvdroxy-2-r4-hvdroxy-3 - was prepared using methods similar to those described in Example 1 x. LCMS RT=2.72 min,
ES+ve 585 (MH)+
Example 23: 4-{(lR)-2-r(6- .4-r3-
({ (Ethylamino)carbonyl]amino>sulfonyl)phenvnbutoxy}hexyl)amino]-l-hvdroxyethv -l- hydroxy-2-(hydroxymethyl)benzene acetate i) 3-r4-((6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl1hexyl)oxy)butvn-N- (ethylamino)carbonyl]benzenesulfonamide
Ethyl isocyanate (0.015g) was added to a stirred mixture of 3-[4-({6-[(5R)-5-(2,2-dimethyl-4H- l,3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide (0.1 lg) and K2C03 (0.055g) in acetone (2ml). The mixture was heated at reflux for 2h then ethyl isocyanate (0.005g) was added. After 0.5h the reaction mixture was cooled and quenched with water (lml). The mixture was partitioned between EtOAc (20ml) and H20 (20ml). The aqueous phase was extracted with EtOAc (20ml). The combined EtOAc phases were washed with brine
(10ml) then dried (Na2S04) and concentrated. The residue was purified by SPE (silica 5g) with CH2C12 (2x15ml), Et20 (2x15ml) and EtOAc (2 xl5ml), evaporation of the EtOAc fractions afforded the title compound (0.061 g). ES+ve 632 (MH)+
ii) 4-{(lR)-2- (6-(4-[3-f{r(Ethylamino)carbonyl1amino}sulfonyl)phenyl]butoxylhexyl)amino1- 1 -hydroxyethyl } - 1 -hvdroxy-2-(hvdroxymethyl)benzene acetate was prepared using methods similar to those described in Example 1 x. LCMS RT=2.86 min, ES+ve 606 (MH)+
Example 24: 3-(4-{r6-({2-Hvdroxy-2-r4-hydroxy-3- (hvdroxymethyl)phenyl]ethyl}amino)hexyl]oxy|butyl)benzenesulfonamide acetate i) tert-Butyl 2-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-hydroxyethylcarbamate Recrystallisation of a batch of 3: 1 (R:S) Example 1 iii (78.94g) gave the title compound (27.6g). LCMS RT=3.31min
ii) 5-(2.2-Dimethyl-4H-l,3-benzodioxin-6-yl)-1.3-oxazolidin-2-one was prepared using methods similar to those described in Example 1 iv. ES+ve 250 (MH)+
iii) 3-r6-(But-3-vnyloxy)hexyl]-5-(2.2-dimethyl-4H-l,3-benzodioxin-6-yl)-l,3-oxazolidin-2-one was prepared using methods similar to those described in Example 1 vi. ES+ve 402 (MH)+
iv) 3-r4-({6-r5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-L3-oxazolidin-3- yl]hexyl } oxy)but- 1 -ynyllbenzenesulfonam ide was prepared using methods similar to those described in Example 1 vii. ES+ve 557 (MH)+
v) 3-r4-({6-r5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexyl}oxy)butyl]benzenesulfonamide was prepared using methods similar to those described in Example 1 viii. ES+ve 561 (MH)+
vi) 3- .4-r ( 6- { r2-(2.2-Dimethyl-4H- 1 ,3-benzodioxin-6-yl)-2- hvdroxyethyl]amino)hexyl)oxy]butyl)benzenesulfonamide was prepared using methods similar to those described in Example 1 ix. ES+ve 535 (MH)+
vii) 3-.4- . !6-f .2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyl1ethyl|amino)hexyl1oxylbutyl)benzenesulfonamide acetate was prepared using methods similar to those described in Example 1 x. LCMS RT=2.90 min,
ES+ve 495 (MH)+
Example 25: 3-(4- { r6-( ,(,2S)-2-Hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl ,phenyl]ethyl)amino)hexyl^oxy}buWl)benzenesulfonamide acetate
3- (4-IY6- ( r(2S)-2-f 2.2-Dimethyl-4H- 1.3-benzodioxin-6-yl)-2- hydroxyethvπamino. hexyDoxylbutyl . benzenesulfonamide Resolution of 3- {4-[(6- { [2-(2,2-dimethyl-4H- 1 ,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl} benzenesulfonamide (0.403g) on an HPLC Chiralcel OJ column using 40% ethanol/heptane afforded the title compound (0.096g).
ii) 3-(4-(r6- C2S)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenvnethvUamino)hexylloxy}butyl)benzenesulfonamide acetate was prepared using methods similar to those described in Example 1 x. LCMS RT=2.44 min,
ES+ve 495 (MH)+
Example 26: N-I -. .1X4- . re-f .dR.^-Hvdroxy^-K-hvdroxy-S-
Figure imgf000052_0001
acetate i) N-(4-r. (3-r4-f(6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl1hexyl)oxy)but-l-vnyllphenyl>sulfonyl)amino]phenyl}acetamide was prepared using methods similar to those described in Example 1 vii. ES-ve 688 (M-HV
• ii) N-(4-r 3-r4-({6-r(,5R)-5-f2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl1hexy oxy)butyl]phenyUsulfonyl)amino]phenyl}acetamide was prepared using methods similar to those described in Example 1 viii. ES-ve 692 (M-HV
iii) N-(4-{r(3-{4-I(6-(r(,2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroxyethyl]amino}hexyl)oxylbutyUphenyl)sulfonyl1amino)phenyl)acetamide was prepared using methods similar to those described in Example 1 ix. ES+ve 668 (MH)+
iv) N-r4-((I3-(4-(r6-r((2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyl1ethyl}amino)hexyl1oxy}butyl)phenyl]sulfonyl|amino)phenyl1acetamide acetate GW671337A R5965/48/1 1 was prepared using methods similar to those described in Example 1 x. LCMS RT=2.59 min,
ES+ve 628 (MH)+
Example 27: N-Cvclobutyl-3-.4- . r6-( _(2R)-2-hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl)phenyl]ethv amino)hexyl]oxy>butyl)benzenesulfonamide acetate (i) N-Cvclobutyl-3-r4-((6-r(5R)-5-.2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3- oxazolidin-3-yl]hexyl}oxy)but-l-ynyl]benzenesulfonamide was prepared using methods similar to those described in Example 1 vii. ES+ve 61 1 (MH)+
ii) N-Cvclobutyl-3-r4-('(6-r(5R)-5-('2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3- oxazolidin-3-yl1hexyl . oxy)butvHbenzenesulfonamide was prepared using methods similar to those described in Example 1 viii. ES+ve 615 (MH)+
iii) N-Cvclobutyl-3-(4-r(6-{r(2R)-2-.2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroxyethyl]amino)hexyl)oxy1butyl . benzenesulfonamide was prepared using methods similar to those described in Example 1 ix. ES+ve 589 (MH)+
iv) N-Cvclobutyl-3-(4-(r6-f(('2R)-2-hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyl1ethyl . amino)hexyl1oxy>butyl)benzenesulfonamide acetate was prepared using methods similar to those described in Example 1 x. LCMS RT=2.72 min, ES+ve 549
(MH)+
Example 28: N-Cvclohexyl-3-.4-{r6-( ,(2R)-2-hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl]ethyl , amino)hexyl]oxy. butyl)benzenesulfonamide acetate i) N-Cyclohexyl-3 -\4-( j 6- . (5R)-5 -(2.2-dimethyl-4H- 1.3 -benzodioxin-6-yl)-2-oxo- 1.3- oxazolidin-3-yl]hexyl>oxy)but-l-vnyl]benzenesulfonamide was prepared using methods similar to those described in Example 1 vii. ES+ve 639 (MH)+
i i) N-Cvclohexyl-3 -\4-( , 6-. (5R)-5 -(2.2-dimethyl-4H- 1.3 -benzodioxin-6-yl)-2-oxo- 1.3- oxazolidin-3-yllhexyl. oxy)butyl]benzenesulfonamide was prepared using methods similar to those described in Example 1 viii. ES+ve 643 (MH)+
iii) N-Cvclohexyl-3-(4-r(6-(r(2R)-2-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroxyethyl]amino . hexyl)oxy]butyl . benzenesulfonamide was prepared using methods similar to those described in Example 1 ix. ES+ve 617 (MH)+
iv) N-Cvclohexyl-3-(,4-(r6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl]ethv amino)hexyl]oxy. butyl)benzenesulfonamide acetate was prepared using methods similar to those described in Example 1 x. LCMS RT=2.85 min, ES+ve 577 (MH)+
Figure imgf000053_0001
^vdroxymethvOphenyllethv amino^exylloxy. butyl.-N^-moφholin^- ylethvDbenzenesulfonamide acetate i) 3-r4-( .6-[r5R)-5-('2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl1hexy oxy)but-l-vnyll-N-(2-moφholin-4-ylethyl)benzenesulfonamide was prepared using methods similar to those described in Example 1 vii. ES+ve 670 (MH)+
ii) 3-r4-({6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yllhexy oxy)butyl]-N-(2-morpholin-4-ylethyl)benzenesulfonamide was prepared using methods similar to those described in Example 1 viii. ES+ve 674 (MH)+
iii) 3- .4-r(6-(r(2R)-2-('2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-hvdroxyethvn- amino)hexyl)oxy]butyl}-N-(2-moφholin-4-ylethyl)benzenesulfonamide was prepared using methods similar to those described in Example 1 ix. ES+ve 648 (MH)+
iv) 3-r4-(r6-({(2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethyl>- amino)hexyl]oxylbutyl)-N-(2-moφholin-4-ylethyl)benzenesulfonamide acetate was prepared using methods similar to those described in Example 1 x. LCMS RT=2.22 min, ES+ve 608 (MH)+
Example 30: N-r2-(2-Hvdroxyethoxy)ethyll-3-(4-(r6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl)phenyl]ethyl . amino)hexyl]oxylbutyl)benzenesulfonamide i) 3-[4-({6-[(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexyl . oxy)but-l-ynyll-N-.2-(2-hvdroxyethoxy)ethyl1benzenesulfonamide was prepared using methods similar to those described in Example 6 i. ES+ve 645 (MH)+
ii) 3-r4-((6-r('5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yllhexyl, oxy)butyl]-N-[2-(2-hydroxyethoxy)ethyl]benzenesulfonamide was prepared using methods similar to those described in Example 1 viii. ES+ve 647 (MH)"
iii) N-r2-(2-Hvdroxyethoxy)ethyl1-3-(4-{r6-. {(2R)-2-hydroχy-2-r4-hvdroxy-3- (hydroxymethyl)phenyl1ethyl . amino)hexyl]oxy. butyl)benzenesulfonamide was prepared using methods similar to those described in Example 14 v. LCMS RT=2.62 min, ES+ve 583 (MH)+
Example 31: N-(4-Fluorophenyl)-3-(4-{r6-( .(2R)-2-hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl )phenyll ethyl > am i no)hexyll oxy } butvDbenzenesulfonamide acetate i) 3-[4-({6- (5R)-5-(2,2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexyl . oxy)but-l-vnyll-N-(4-fluorophenyl)benzenesulfonamide was prepared using methods similar to those described in Example 1 vii. ES+ve 651 (MH)+
ii) 3-r4-((6-r(5R)-5-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl1hexyπoxy)butyl]-N-(4-fluorophenyl)benzenesulfonamide was prepared using methods similar to those described in Example 1 viii. ES+ve 655 (MH)+
iii) 3-(4- (6-( (2R)-2-('2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroxyethyllaminolhexyl)oxy1butyl>-N-(4-fluorophenyl)benzenesulfonamide was prepared using methods similar to those described in Example 1 ix. ES+ve 629 (MH)+
iv) N-(4-Fluorophenyl)-3-C4-(r6-(' . ('2R)-2-hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl)phenyl1ethvπamino)hexylloxy>butyl)benzenesulfonamide acetate was prepared using methods similar to those described in Example 1 x. LCMS RT=2.81 min,
ES+ve 589 (MH)+
Example 32: N-r4-(Aminosulfonyl)phenyl1-3-.4-(r6-(((2R)-2-hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl1ethyl)amino)hexyl]oxy, butyl)benzenesulfonamide acetate i) N-r4-.Aminosulfonyl)phenyll-3-r4-('{6-r(5R)-5-('2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2- oxo-1.3-oxazolidin-3-yl1hexyπoxy)but-l-vnyl]benzenesulfonamide was prepared using methods similar to those described in Example 1 vii. ES+ve 712 (MH)+ ii'> N-r4-rAminosulfonyl)phenyl1-3-r4-({6- .5R)-5-('2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2- oxo-1.3-oxazolidin-3-yl]hexyUoxy)butyllbenzenesulfonamide was prepared using methods similar to those described in Example 1 viii. ES+ve 716 (MH)+
iii) N-r4-(Aminosulfonyl)phenyll-3-(4-r(6-( (2R)-2-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2- hydroxyethyl1amino}hexyl)oxy]butyl)benzenesulfonamide was prepared using methods similar to those described in Example 1 ix. ES+ve 690 (MH)+
iv) N-r4-(Aminosulfonyl)phenvn-3-.4-(r6-f{(2R)-2-hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl1ethyl . amino)hexyl]oxy. butyl)benzenesulfonamide acetate was prepared using methods similar to those described in Example 1 x. LCMS RT=2.61 min, ES+ve 650 (MH)+
Example 33: 2-(Hvdroxymethyl)-4- {( 1 R)- 1 -hvdroxy-2-r(6- , 4-f 3-(piperazin- 1 - ylsulfonyl)phenyl]butoxylhexyl)aminolethvU phenol acetate i) .5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-3-r6-(l4- 3-fpiperazin-l- ylsulfonyl)phenyllbut-3-ynv oxy)hexyl1-l,3-oxazolidin-2-one was prepared using methods similar to those described in Example 1 vii. ES+ve 626 (MH)+
Figure imgf000055_0001
ylsulfonyl)phenyl]butoxy)hexyl)-1.3-oxazolidin-2-one was prepared using methods similar to those described in Example 1 viii. ES+ve 630 (MH)+
iii) (lR)-l-(2.2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2-r(6-{4-[3-(piperazin-l- yl su lfonyl ) pheny 1] butoxy} hexy Damino] ethano 1 was prepared using methods similar to those described in Example 1 ix. ES+ve 604 (MH)+
iv) 2-(Hvdroxymethyl)-4- {( 1 R)- 1 -hydroxy-2-IY 6- (4-r3-(piperazin- 1 - ylsulfonyl)phenyl]butoxy>hexyl)amino]ethyl)phenol acetate was prepared using methods similar to those described in Example 1 x. LCMS RT=2.23 min,
ES+ve 564 (MH)+
Example 34: 3-C4- . f6-(,((2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl)phenyl]ethy amino)hexyl1oxylbutyl)-N-fl-methyl-l- phenylethyDbenzenesulfonamide acetate i) 3-r4-r(6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexy oxy)but- 1 -ynyl]-N-( 1 -methyl- 1 -phenylethyDbenzenesulfonamide was prepared using methods similar to those described in Example 1 vii. ES-ve 673 (M-HV
ii) 3-r4-((6-r(5R)-5-(,2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexyUoxy)butyl1-N-(l -methyl- 1 -phenylethyDbenzenesulfonamide was prepared using methods similar to those described in Example 1 viii. ES-ve 677 (M-H)" iii) 3-(4-r(6- . r('2R)-2-('2.2-Dimethyl-4H-1.3-benzodioxin-6-vD-2-hvdroxyethyll- amino. hexy Doxyl butyl) -N-(l -methyl- 1 -phenylethyDbenzenesulfonamide was prepared using methods similar to those described in Example 1 ix. ES+ve 653 (MH)+
iv) 3-(4-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenvnethyl>- amino)hexylloxy. butyl)-N-(l -methyl- 1 -phenylethyDbenzenesulfonamide acetate was prepared using methods similar to those described in Example 1 x. LCMS RT=2.90 min, ES+ve 613 (MH)+
Example 35: 5-f4-(r6-('(f2R)-2-Hvdroxy-2-r4-hvdroxy-3-fhvdroxymethvD- phenvπethyl _ amino)hexyl1oxy_ butyl)-2-methoxybenzenesulfonamide acetate i) 5-r4-({6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexyl . oxy)but- 1 -vnyl]-2-methoxybenzenesulfonamide was prepared using methods similar to those described in Example 1 vii. ES+ve 587 (MH)+
ii) 5-[4-({6-[(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexyUoxy)butyl]-2-methoxybenzenesulfonamide was prepared using methods similar to those described in Example 1 viii. ES+ve 591 (MH)+
iii) 5- .4-r(6- ( r(2R)-2-('2.2-Dimethyl-4H- 1.3-benzodioxin-6-yl)-2- hydroxyethyllamino}hexyl)oxy]butyl>-2-methoxybenzenesulfonamide was prepared using methods similar to those described in Example 1 ix. ES+ve 565 (MH)+
iv) 5-(4- . r6-(- ,f2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hydroxymethvDphenyl]ethvUamino)hexyl1oxy>butyl)-2-methoxybenzenesulfonamide acetate was prepared using methods similar to those described in Example 1 x. LCMS RT=2.41 min, ES+ve 525 (MH)+
Example 36: (E)-2-f3-(4-{r6-( .(2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl)phenyllethyUamino)hexyl]oxy}butyl)phenyl]-N-methylethenesulfonamide i) 4-(3-Bromophenyl)but-3-yn- 1 -ol
A stirred, cooled solution of l-bromo-3-iodobenzene (31g) and 3-butyn-ol (7ml) in acetonitrile (100ml) and triethylamine (100ml) was purged with nitrogen for 20min under nitrogen. Dichlorobis(triphenylphosphine)palladium (500mg) and cuprous iodide (800mg) were added. The mixture was stirred for 18h and then the solvent was removed m-vacuo. The residual oil was triturated with ethyl acetate (200ml) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on Biotage (90g) eluting with light petroleum 40- 60° - diethyl ether (3:2) to give the title compound (21g). LCMS RT=3.26min.
ii) 4-.3-Bromophenyl)butan-l-ol
A solution of 4-(3-bromophenyl)but-3-yn-l-ol (21g) in ethanol (1000ml) was hydrogenated over platinum oxide (500mg) for 4h. The catalyst was removed by filtration and the filtrate was evaporated to give the title compound (18g) tic (Si02) diethyl ether Rf=0.38. iii) l-Bromo-3-{4-[(6-bromohexyl)oxy1butvP benzene
A stirred mixture of 4-(3-bromophenyl)butan-l-ol (18g) and 1,6 dibromohexane (48ml) in 50% aq. sodium hydroxide (500ml) with tetrabutylammonium bromide (1.5g) was stirred for 2d at 20°. The mixture was poured into water (1000ml) and extracted into ethyl acetate (3x 500ml). The combined extracts were washed with water (1000ml), dried (Na2S04 ). The solvent was removed in-vacuo and the residual oil was purified by flash chromatography (500g) using dichloromethane as eluent, changing to light petroleum (40-60°)-diethyl ether (9: 1) to give the title compound ( 18g). LCMS RT=4.34min.
iv) (5R)-3-(6-[4-(3-BromophenyDbutoxy1hexyl . -5-,2.2-dimethyl-4H-l ,3-benzodioxin-6-vD- 1.3-oxazolidin-2-one
Sodium hydride (60% dispersion in oil, 690mg) was added to a stirred solution of 5R-(2,2- dimethyl-4H-l,3-benzodioxin-6yl)-l,3-oxazolidin-2-one (3.0g) in dry DMF (35ml) at 5°C under nitrogen. After 20min a solution of l-bromo-3-{4-[(6-bromohexyl)oxy]butyl}benzene (5.64g) in dry DMF (15ml) was added. The mixture was stirred at ambient temperature for 4h. The mixture was poured into an ammonium chloride solution (300ml) and extracted into ethyl acetate (3x100ml). The combined extracts were washed with water (200ml), dried (Na2S04) and evaporated. The residual oil was purified by chromatography on Biotage (90g) eluting with diethyl ether-light petroleum (bp 40-60) (4: 1) to give the title compound (5.2g). LCMS
RT=4.13min.
v) (E)-2-{3-r4-({6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexyUoxy)butyllphenvU-N-methylethenesulfonamide A stirred mixture (5R)-3-{6-[4-(3-bromophenyl)butoxy]hexyl}-5-(2,2-dimethyl-4H-l,3- benzodioxin-6-yl)-l,3-oxazolidin-2-one (l .Og), N-methylethenesulphonamide (WO 95/09166), (462mg), tri-otolylphosphine (200mg), palladium acetate (165mg) and triethylamine (5ml) in dry DMF (15ml) was heated at 90°C for 18h. The mixture was cooled and filtered. The filtrate was poured into water (200ml) and extracted into ethyl acetate (3x50ml). The combined extracts were washed with water (100ml) and (Na2S04) and evaporated in vacuo. The residual oil was purified by chromatography on Biotage (40g) eluting with diethyl ether-ethyl acetate (9: 1) to give the title compound (220mg). LCMS RT=3.70min.
vi) (E)-2-.3-{4-r(6-(r(2R)-2- .2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxylbuWl . phenyD-N-methylethenesulfonamide
Was prepared using methods similar to those described in Example lix. LCMS RT=2.96min
vii) (E)-2-.3-(4-{r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenvnethyl)amino)hexyl]oxy>butyl)phenyl]-N-methylethenesulfonamide
A solution of (E)-2-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)-N-methylethenesulfonamide (lOOmg) in methanol (15ml) was administered onto a Bond Elut SCX2 cartridge (lOg) , which had been preconditioned in methanol. The cartridge was eluted with methanol (2x25ml) followed by 15% aq. ammonia-methanol (2x20ml). Evaporation of the latter fractions gave the title compound (70mg) LCMS RT=2.59min, ES+ve 535 (MH )+
viii) (E)-2-r3-(4-(r6-. ((2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hydroxymethyl)phenyllethyl}amino)hexyl]oxy}butyDphenyll-N-methylethanesulfonamide compound with (2E)-but-2-enedioic acid (1 : 1) A solution of (E)-2-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-N-methylethenesulfonamide
(60mg) and fumaric acid (6.5mg) in ethanol was evaporated to dryness to give the title compound (66mg) LCMS RT=2.65 min, ES+ve 537 (MH)+
Example 37: 2-.3-(4- . r6-( ( (2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hydroxymethvDphenyl]ethyl)amino)hexyl]oxy}butyl)phenyl]ethanesulfonamide i) tert-Butyl vinylsulfonylcarbamate
Di-tert-butyldicarbonate (8.62g) was added to a stirred, cooled (ice bath) solution of ethenesulphonamide (S. Hirooka, Bull. Chem. Soc. Jpn. 1991, 64, 1431) (3.4g ), 4- (dimethylamino)pyridine (410mg) and triethylamine (7ml) in dichloromethane (40ml) under nitrogen. The solution was stirred for 30min, washed with 2M hydrochloric acid (30ml), water
(50ml) and dried (Na2S04) to give the title compound (5.0%). Tic (Si02, 1:1 diethyl ether- cyclohexane) Rf=0.4.
ii) (E)-2-(3-r4-( .6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl1hexyl}oxy)butyl]phenyl)ethenesulfonamide
Was prepared using methods similar to those described in Example 36 v. LCMS RT=3.6 min
iii) (E)-2-(3-(4-r(6-(r(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hydroxyethyl1amino)hexyl)oxy1butyl)phenyl)ethenesulfonamide Was prepared using methods similar to those described in Example 1 ix.
LCMS RT=2.87 min
iv) (EV2-.3 -(4- j r6-( ((2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hydroxymethyl)phenyllethyl>amino)hexyl]oxylbutyl)phenyl]ethenesulfonamide Was prepared using methods similar to those described in Example 1 x.
LCMS RT=2.55min
v) 2-r3-(4-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyl1ethyl)amino)hexyl]oxylbutyl)phenyl]ethanesulfonamide Was prepared using methods similar to those described in Example 1 viii.
LCMS RT=2.73min, ES+ve 523 (MH)+ Example 38: 5-(4-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hydroxymethyl)phenyl1ethvUamino)hexyl1oxy}butyl)ri.r-biphenyl]-3-sulfonamide acetate i) tert-Butyl (3.5-diiodophenyl)sulfonylcarbamate
Di tert-butyl dicarbonate(l .l lg) was added to a stirred solution of 3,5 di-iodo- benzenesulfonamide (Tsatsas, Chem. Chron. 1974, 3, 143) (1.6g), 4-(dimethylamino)pyridine
(50mg) and triethylamine(0.8ml) in dichloromethane (30ml) at 5°. The solution was stirred at ambient temperature for lh, washed with IM hydrochloric acid (30ml), water (50ml) and dried (Na2S04). The solvent was evaporated to give the title compound (1.6g). LCMS RT=4.24min.
ii) tert-Butyl (3.5-diiodophenvDsulfonyU[2-(trimethylsilyl)ethoxy1methvU carbamate
Sodium hydride (60% dispersion in oil, 157mg) was added to a stirred solution of tert-butyl (3,5- diiodophenyl)sulfonylcarbamate (1.6g) in DMF (10ml) at 5° under nitrogen. After lOmin 2- (trimethylsilyl)ethoxymethyl chloride (0.61ml) was added. The mixture was stirred for 30min. The reaction mixture was poured into aq. ammonium chloride (100ml) and extracted into diethyl ether (3x40ml). The organic extracts were washed with water (30ml), dried (Na2S04) and evaporated to give the title compound (\ .95%). LCMS RT=4.47min.
iii) tert-Butyl .3-r4-((6-r(5R)-5-(2.2-dimethyl-4H- 1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3-yl]hexyUoxy)but-l-ynyl]-5- iodophenyl } sul fon yl{ 2-(trimeth yl s i 1 yl )ethoxy] methyl } carbamate
A solution of (5R) 3-[6-(but-3-ynyloxy)hexyl]-5-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)-l,3- oxazolidin-2-one (233mg) and tert-butyl (3,5-diiodophenyl)sulfonyl{[2- (trimethylsilyl)ethoxy]methyl}carbamate (410mg) in dry acetonitrile (3ml) and triethylamine(3ml) was purged with nitrogen for 30min. Cuprous iodide (50mg) and dichlorobis(triphenylphosphine)palladium (50mg) were then added. The mixture was stirred for
18h at ambient temperature and then evaporated to dryness. The residual oil was purified by chromatography on Biotage (8g) eluting with diethyl ether-petroleum ether (bp 40-60°). The appropriate fractions were evaporated to give the title compound (190mg). LCMS RT=4.54min.
iv) 3- ((tert-Butoxycarbonyl){r2-(trimethylsilyl)ethoxylmethyl)amino)sulfonyl]-5-[4-({6-[(5R)-
5-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-L3-oxazolidin-3-yl]hexyUoxy)but-l-ynyl]- l.l'-biphenyl
A stirred mixture of tert-butyl {3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)-2-oxo- l,3-oxazolidin-3-yl]hexyl}oxy)but-l-ynyl]-5-iodophenyl}sulfonyl{[2- (trimethylsilyl)ethoxy]methyl} carbamate (190mg), benzeneboronic acid (62mg) in dimethoxyethane (4ml) and IM sodium carbonate (2ml) with tetrakis(triphenylphosphine)palladium(0) (25mg) was heated at 80° for lh. The mixture was poured into water (20ml) and extracted into ethyl acetate (3x30ml). The organic extracts were dried (Na2S04) and evaporated. The residual oil was purified by chromatography on Biotage (8g) eluting with cyclohexane-diethyl ether (4:1) to give the title compound (140mg). LCMS
RT=4.54 min. v) 3-["((tert-Butoxycarbonyl){r2-(trimethylsilvDethoxylmethvUamino)sulfonyl]-5-r4-({6- (5R)-
5-(2.2-dimethyl-4H- 1.3-benzodioxin-6-yl)-2-oxo- 1 ,3-oxazolidin-3-yl]hexyl ) oxy)butyl]- 1.1'- biphenyl was prepared using methods similar to those described in Example 1 viii.
LCMS RT=4.55min.
vi) 5-(4-r(6-(r(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroxyethyl]amino. hexyDoxy1butyl) l. -biphenyll-3-sulfonamide
Was prepared using methods similar to those described in Example 1 ix. LCMS RT=2.86min.
vii) 5-(4-(I6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hydroxymethyl)phenyl]ethyUamino)hexyl1oxy}butyl) L -biphenyl1-3-sulfonamide acetate Was prepared using methods similar to those described in Example 1 x. LCMS RT=2.76min,
ES+ve 571(MH)+.
Example 39: 3-(4-{r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-(hvdroxymethyl)phenyllethyl)- amino)hexyl]oxy, butyl)-5-pentylbenzenesuIfonamide acetate i) tert-Butyl {3-r4-((6-r(5R)-5-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl] hexyl ) oxy)but- 1 -ynyl] -5 -pent- 1 -ynylphenyl } sulfonyl { [2- (trimethylsilyl)ethoxy]methyDcarbamate
Was prepared using methods similar to those described in Example 1 vii. LCMS RT=4.77min.
ii) tert-Butyl π-[4-((6-[(5R)-5-(2.2-dimethyl-4H-L3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin- 3-yl]hexyl}oxy)butyl]-5-pentylphenyl . sulfonvUr2-(trimethylsilyl)ethoxy]methyUcarbamate Was prepared using methods similar to those described in Example 1 viii. LCMS RT=4.7min.
iii) 3-(4-.(6-{r(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-vP-2- hydroxyethyl]amino}hexyl)oxy]butyl)-5-pen.ylbenzenesulfonamide
Was prepared using methods similar to those described in Example 1 ix. LCMS RT=3.21min.
iv) 3-(4- { [6-( {(2R)-2-Hvdroxy-2-[4-hydroxy-3-(hydroxymethyDphenyl]ethyl } - amino)hexyl]oxy)butyl)-5-pentylbenzenesulfonamide acetate
Was prepared using methods similar to those described in Example 1 x
LCMS RT=2.93min, ES+ve 565 (MH )+
Example 40: 3-(4- . f6-( . (2R)-2Hvdroxy-2-r4-hvdroxy-3-
(hydroxymethyl)phenyl]ethyl } aminohexylloxy) butyPbenzenesulfo namide
(i) 6-(But-3-vnyloxy)hexanal 6-Bromohexylbut-3-ynyl ether (DE3513885A1) (525mg) in DMSO (2ml) was added to a mixture of sodium bicarbonate (lg) in DMSO (8ml) at 150°C with vigorous stirring and nitrogen bubbling through the solution. The mixture was stirred for 20 min at 150 °C and then allowed to cool to room temperature, diluted with diethyl ether and washed with water. The aqueous layer was extracted with diethyl ether and the combined ether layers were washed with dilute hydrochloric acid, brine, dried (MgS04) and evaporated to dryness to give the title compound (325mg): IR 1726 cm"1 MS(TSP+ve) m/z 186 (M+MH^-
(ii) ( lR)-2-( r6-(But-3-ynyloxy)hexyl] [( 1 S)-2-hvdroxy- 1 -phenylethyl]amino) - 1 -(2.2-dimethyl-
4H-1.3-benzodioxin-6-yl)ethanol
A mixture of 6-(but-3-ynyloxy)hexanal (434mg) and (lR)-l-(2,2-dimethyl-4H-l,3-benzodioxin- 6-yl)-2-{[(lS)-2-hydroxy-l-phenylethyl]amino}ethanol (710mg) (WO/0196278) in chloroform (10ml) was treated at 20°C with sodium triacetoxyborohydride (866mg) and stirred under nitrogen for 2 days. The mixture was diluted with ethyl acetate and aqueous sodium bicarbonate solution. The organic phase was separated and washed with sodium bicarbonate solution, brine, dried and purified on a silica Bond Elut cartridge (lOg) eluting with dichloromethane, diethyl ether and finally ethyl acetate to give the title compound (810mg): LCMS RT=2.69min, ES+ve m/z 496 (M+Η)+.
(iii) 3-(4-r(6- . r(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-hvdroxyethvHr(lS)-2- hydroxy-l-phenylethyl]amino}hexyl)oxy]but-l-yny benzenesulfonamide was prepared using methods similar to those described in Example 1 vii. LCMS RT=2.85min
(iv) 3-(4- . r6-( .(2R)-2Hvdroxy-2-.4-hvdroxy-3-
(hydroxymethyl)phenyl]ethyl}aminohexyl]oxy)butyl)benzenesulfonamide
3- {4-[(6- { [(2R)-2-(2,2-Dimethyl-4H- 1 ,3-benzodioxin-6-yl)-2-hydroxyethyl] [( lS)-2-hydroxy- 1 - phenylethyl]amino}hexyl)oxy]but-l-ynyl}benzenesulfonamide (104mg) was hydrogenated in ethanol (50ml) over Pearlman's catalyst (60mg) over 4h and then over 10%Pd/C (lOOmg) over 4 days. The catalyst was removed by filtration and washed with ethanol. The filtrate was concentrated and then applied to an SCX-2 cartridge eluting with methanol, followed by 0.67M ammonia in methanol. The ammonia fractions were concentrated and purified by chromatography on Biotage (4g cartridge) eluting with dichloromethane-methanol-2M ammonia in methanol (50:8: 1 ) to give the title compound (\ 1 mg) LCMS RT=2.34min ES+ve 495 (M+H)+.
Example 41: 3-Fluoro-5-(4-{.6-( .(2R)-2-hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl]ethyl)amino)hexyl]oxy. butyl)benzenesulfonamide i) 3-Fluoro-5-iodobenzenesulfonamide
3-Fluoro-5-iodoaniline (3.06g) (WO 9623783) was added to a stirred mixture of concentrated hydrochloric acid (4ml) and water (4ml). Glacial acetic acid (8ml) was added and the reaction mixture cooled to -5°C. A solution of sodium nitrite (0.99g) in water (8ml) was added dropwise maintaining the temperature between -5°C and -2°C. After the addition was complete the reaction was stirred for lOmin. In the meantime glacial acetic acid (20ml) was saturated with sulfur dioxide gas for 0.25h, then copper(I) chloride (0.353g) was added. Additional sulfur dioxide was bubbled through the solution until a fine suspension was obtained. The mixture was cooled to 5°C and then treated portionwise with the diazonium salt prepared above. After stirring at room temperature for lh ice (50g) was added. The mixture was extracted with ether (100ml) and the organic phases washed with NaHC03 solution (2 100ml) then water ( 100ml), dried ( MgS04) and concentrated. The residue was dissolved in THF (30ml) at 0°C and aqueous ammonia (0.880; 5ml) was added. After stirring at room temperature the mixture was partitioned between EtOAc (100ml) and water (100ml). The organic phase was washed with brine (50ml), dried (MgS04) and concentrated. The residue was purified by chromatography using cyclohexane-EtOAc (5: 1 then 3: 1). Evaporation of the fractions and trituration of the residue with cyclohexane afforded the title compound (0.886g). ES-ve 299 (M-H)"
i i) 3 -!4-( ( 6-IY5R)-5 -(2,2-Dimethyl-4H- 1.3 -benzodioxin-6-yl)-2-oxo- 1.3 -oxazol idin-3 - yl1hexyl)oxy)but-l-vnyll-5-fluorobenzenesulfonamide was prepared using methods similar to those described in Example 1 vii. ES+ve 575 (MH)+
iii) 3- 4-({6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl1hexyDoxy)butyl1-5-fluorobenzenesulfonamide was prepared using methods similar to those described in Example 1 viii. ES+ve 579 (MH)+
iv) 3 - 14-rf 6- . IT2R )-2-(2.2-Dimethyl-4H- 1.3 -benzodioxin-6-yl)-2- hvdroxyethyl amino>hexyl)oxy]butyU-5-fluorobenzenesulfonamide was prepared using methods similar to those described in Example 1 ix. ES+ve 553 (MH)+
v) 3-Fluoro-5-(4- ..6-( .(2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethvDphenyl1ethvUamino)hexyl1oxy}butyl)benzenesulfonamide was prepared using methods similar to those described in Example 36 vii. LCMS RT=2.50 min,
ES+ve 513 (MH)+
Example 42: 5-(4- . r6-( .(2R)-2-Hydroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl]ethyUamino)hexyl]oxy)butyD-3-trifluoromethylbenzenesulfonamide i) 3-Bromo-5-trifluoromethylbenzenesulfonamide was prepared using methods similar to those described in Example i. ES-ve 302,304 (M-H)"
ii) 3-r4-((6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-vD-2-oxo-1.3-oxazolidin-3- yl1hexyl , oxy)but-l-vnvπ-5-(trifluoromethyl)benzenesulfonamide was prepared using methods similar to those described in Example 6 i. ES+ve 625 (MH)+
iii) 3-|"4-((6- (5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-l,3-oxazolidin-3- vπhexyUoxy)butyl .-5-trifluoromethylbenzenesulfonamide was prepared using methods similar to those described in Example 1 viii. ES+ve 629 (MH)+
iv) 3-{4_r(6-(r(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroxyethvnamino)hexyl)oxy]butyl)-5-(trifluoromethyl)benzenesulfonamide was prepared using methods similar to those described in Example 1 ix. ES+ve 603 (MH)+
v) 3-(4-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethvDphenvnethvUamino)hexyl1oxy)butvD-5-(trifluoromethyl)benzenesulfonamide was prepared using methods similar to those described in Example 36 vii. LCMS RT=2.57 min,
ES+ve 563 (MH)+
Example 43: 3-(4- { r6-( .(2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethyl)phenyl]ethvUamino)hexylloxy)butyl)-5-methylbenzenesulfonamide acetate i) 3-Bromo-5-methylbenzenesulfonamide was prepared from 3-bromo-5-methylaniline (EP303387A1) using methods similar to those described in Example 41(i). LCMS RT = 2.80 min
ii) 3 -\4-( { 6-IY5R.-5 -(2.2-Dimethyl-4H- 1.3 -benzodioxin-6-yl)-2-oxo- 1.3 -oxazol idin-3 - yl]hexyUoxy)but-l-vnyl]-5-methylbenzenesulfonamide was prepared using methods similar to those described in Example 1 vii. LCMS RT = 3.54 min
iii) 3-r4-((6- (5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexyUoxy)butvn-5-methylbenzenesulfonamide was prepared using methods similar to those described in Example 1 viii. LCMS RT = 3.60 min
iv) 3- .4-,(6- . r(2R)-2-(2.2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2- hvdroxyethyl]amino>hexyDoxy]butyl>-5-methylbenzenesulfonamide was prepared using methods similar to those described in Example 1 ix. LCMS RT = 2.73 min
v) 3-(4-{r6-({(2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenyllethvUamino)hexyl1oxy>butyl)-5-methylbenzenesulfonamide was prepared using methods similar to those described in Example 1 x. LCMS RT = 2.43 min, ES +ve 509 (MFT)
Example 44: N- ..3-(4- . r6-( .(2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hydroxymethyl)phenvHethvUamino)hexyHoxy)butyl)phenyllsulfonyl} glycine acetate
N2-.(3-Iodophenyl)sulfonyl]glvcinamide
(3-Iodophenyl)sulphonyl chloride (0.303g) was stirred with glycinamide hydrochloride (0.122g) and diisopropylethylamme (0.3ml) in DMF (4ml) at 21°for 24h. The mixture was evaporated to dryness and applied to a silica Bond Elut Cartridge (lOg). The cartridge was eluted with CH2C12, Et20 and EtOAc. This gave the title compound (0.146g), LCMS RT=2.36min, ES+ve 341
(MH)+ ii) N2-((3-r4-((6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl .hexyl)oxy)but-l-vnvnphenyl_ sulfonyl)glvcinamide was prepared using methods similar to those in Example 1 vii LCMS RT=3.26min, ES+ve 614
(MH)+
iii) N2-(n-r4-({6-r(5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxo-1.3-oxazolidin-3- yl]hexyl)oxy)butyllphenyl}sulfonyl)glycinamide was prepared using methods similar to those in Example 1 viii LCMS RT=3.23min, ES+ve 618
(MΗ)+
iv) Ν-.f 3- .4-.(6- { r(2R)-2-(2.2-Dimethyl-4H- 1.3-benzodioxin-6-yl)-2- hvdroxyethyl]aminolhexyl)oxylbutvUphenyl)sulfonyl1glycine was prepared using methods similar to those in Example 1 ix LCMS RT=2.70min, ES+ve 593
(MH)+
v) Ν-(r3-(4- . r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethyl)phenvnethyUamino)hexyl]oxy)butyl)phenvnsulfonyllglycine acetate was prepared using methods similar to those in Example 1 x LCMS RT=2.38min, ES+ve 553 (MH)+
Example 45: 3-(4-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3- (hvdroxymethvDphenyl]ethyπamino)hexyl1oxy)butyl)benzenesulfonamide
(i) 6-Bromohexyl but-3-ynyl ether
A mixture of 50% w/v aqueous sodium hydroxide (2500ml), 1,6-dibromohexane (2610g) and tetra-butylammonium bromide (25g) was warmed to 50°C, with stirring. But-3-yn-l-ol (500g) was then added to the reaction mixture at such a rate as to ensure the content's temperature did not exceed 65°C. The reaction was left at 50°C overnight before being cooled to room temperature. Tert-butyl methyl ether (2500ml) and brine (2000ml) was added to the cooled mixture and the layers allowed to separate. The ethereal layer was washed with water (2x2000ml), brine (1x2000ml), and then dried over anhydrous MgS04. The solution was filtered and concentrated under reduced pressure to give crude product as a liquid. This was further purified by fractional distillation using a 60cm vacuum jacketed Vigreux column at ca. 0.5mbar. The product was obtained in the fraction which boiled at 92-98°C, to give the title compound (518g), LC RT = 6.16, δ (CDC13) 3.55 (2H, t, J 6.9Hz), 3.46 (2H, t, J 6.9Hz), 3.41 (2H, t, J 6.9Hz), 2.46 (2H, dt, J 2.5, 6.9Hz), 1.98 (IH, t, J 2.5Hz), 1.86 (2H, m), 1.59 (2H, m), 1.46 (2H, m), 1.38 (2H, m).
(ii) 3-{4- (6-BromohexyDoxy1but-l-ynvUbenzenesulfonamide
A mixture of 3-bromo-benzenesulfonamide (625g), 6-bromohexyl but-3-ynyl ether (850. lg), bis(triphenylphosphine)palladium (II) chloride (62.5g), triphenylphosphine (18.1g) and triethylamine (536.3g) in tetrahydrofuran (6250ml) was stirred under an atmosphere of nitrogen for 20 mins. Copper (I) iodide (12.5g) was then added to give a dark red/brown mixture that was heated to 50°C for 23h. The reaction mixture was then cooled to room temperature and filtered through a short silica pad (lOOOg). The pad was washed with additional tetrahydrofuran (15.6L) and the resulting solution then concentrated under reduced pressure to give crude product (1382g) as a viscous oil. This was purified by chromatography (7kg silica) eluting with 5:1 petroleum etheπethyl acetate followed by 2: 1 petroleum etheπethyl acetate to give the title compound (92,2.9%) as an oil, LC RT = 5.69min, δ (DMSO-d6) 7.79 (IH, s), 7.76 (IH, d, J 7.6Hz), 7.56 (2H, m), 7.42 (2H, m), 3.55 (2H, t, J 6.6Hz), 3.49 (2H, t, J 6.6Hz), 3.42 (2H, t, J 6.6Hz), 2.68 (2H, t, J 6.6Hz), 1.76 (2H, m), 1.50 (2H, m), 1.35 (4H, m).
(iii) 3- .4-[(6-Brornohexyl)oxy]butyD benzenesulfonamide
3-{4-[(6-Bromohexyl)oxy]but-l -ynyl}benzenesulfonamide (627g) in IMS (1900ml) was stirred with activated charcoal (314g) at room temperature for 2h and then filtered through a short pad of Celite. The filter pad was washed with IMS (4300ml) and the filtrate transferred to a hydrogenation vessel. 5% Platinum on Charcoal (520. lg, -50% water) was added and the reaction mixture was then stirred under an atmosphere of hydrogen (0.2 bar) at 20°C for 6 h. The mixture was then filtered through a short pad of Celite and concentrated under reduced pressure to give the title compound (499%) as a solid, LC RT = 5.66, δ (DMSO-d6) 7.65 (IH, s), 7.64 (I H, d, J 9.2Hz), 7.47 (IH, m), 7.42 (IH, m), 7.31 (2H, s), 3.50 (2H, t, J 6.9Hz), 3.34 (4H, m), 2.66 (2H, t, J 7.5Hz), 1.78 (2H, m), 1.62 (2H, m), 1.49 (4H, m), 1.37 (2H, m), 1.30 (2H, m).
(iv) ( 1 R) 2-Bromo- 1 -(2.2-dimethyl-4H- 1 ,3-benzodioxin-6-yl)ethanol
A solution R-diphenylprolinol (75mg) in THF (2ml) was treated with borane-THF (IM, 20.5ml) over 20 min at 20°C under nitrogen. After the addition was complete the solution was kept between 30 and 35°C for lh and then cooled in ice and 2-bromo-l-(2,2-dimethyl-4H-l ,3- benzodioxin-6-yl)ethanone (DE3513885) (3.9g) in THF (10ml) was added over 1.5h keeping the temperature below 5°C. The mixture was stirred under nitrogen for a further 0.5h and then methanol (4ml) was added at 0°C. The solvent was removed under reduced pressure and the residue was purified by chromatography on flash silica gel eluting with ethyl acetate- cyclohexane (1 :4) to give the title compound (3.31%) δ (CDC13) 7.15 (IH, dd, J 8, 2 Hz), 7.03
(IH, br s), 6.82 (IH, d, J 8 Hz), 4.85 (3H, s and m), 3.61 (IH, dd, J 10, 4 Hz), 3.50 (IH, dd, J 10, 9 Hz), 1.54 (6H, s).
(v) (r(lR)-2-Bromo-l-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)ethylloxyUtriethyl)silane Triethylsilyl chloride (205g) was added dropwise to a stirred mixture of (lR)-2-Bromo-l-(2,2- dimethyl-4H-l,3-benzodioxin-6-yl)ethanol (350g) and imidazole (108.5g) in DMF (875ml) at 5°C. Upon complete addition the mixture was warmed to 15°C and stirred, at this temperature for 1 h. N-hexane (3500ml) was then added to the mixture which was washed with water (3x1750ml). The organic layer was dried over anhydrous MgS04 before being filtered and concentrated under reduced pressure to give the title compound (488.6g) as an oil, LC RT = 7.97min, δ (DMSO-d6) 7.18 (IH, d, J 8.2Hz), 7.10 (IH, s), 6.75 (IH, d, J 8.2Hz), 4.83 (IH, m), 4.78 (2H, d, J 6.9Hz), 3.55 (2H, m), 1.45 (6H, s), 0.84 (9H, t, J 8.1Hz), 0.51 (6H, m).
(vi) N-benzyl-N- . (2R)-2-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2- (triethylsilyl)oxy]ethyl . amine
A mixture of {[(lR)-2-Bromo-l-(2,2-dimethyl-4H-l,3-benzodioxin-6- yl)ethyl]oxy}(triethyl)silane (130g) and benzylamine (177ml) in 1,4-dioxane (650ml) was heated at 105°C with stirring overnight. The mixture was then cooled to room temperature and water
(150ml) and diethyl ether (1200ml) added. The layers were separated and the ethereal layer was washed with saturated ammonium chloride solution (3x600ml), saturated sodium bicarbonate solution (200ml) and then brine (200ml). The solution was dried over anhydrous Νa2S04 before being filtered and concentrated under reduced pressure to give the title compound (129.9%) as an oil, LC RT = 5.20min, δ (CDCl3) 7.22 (5Η, m), 7.02 (IH, d, J 8.7Hz), 6.86 (IH, s), 6.68 (IH, d,
J 8.3Hz), 4.75 (2H, s), 4.69 (IH, m), 3.73 (2H, s), 2.70 (2H, m), 1.46 (6H, s), 0.79 (9H, m), 0.44 (6H, m).
(vii) (lR)-2-(Benzylamino)-l-(2.2-dimethyl-4 /-l ,3-benzodioxin-6-yl)ethanol Tetrabutylammonium fluoride (395ml, IM in THF) was added dropwise to a stirred solution of
N-benzyl-N-{(2R)-2-(2,2-dimethyl-4H-l ,3-benzodioxin-6-yl)-2-[(triethylsilyl)oxy]ethyl}amine (129.9g) in TΗF (900ml) at 5°C. Upon complete addition the reaction mixture was maintained at this temperature for 15min before water (600ml) was added. The resulting slurry was diluted with diethyl ether (500ml) and filtered. The filtrate was washed with water (2x500ml) and brine (500ml) before being dried over anhydrous Νa2S04. The resulting mixture was filtered and concentrated under reduced pressure to give a solid which was triturated with diisopropyl ether to give the title compound (10%) as a solid, LC RT = 3.34min, δ (CDC13) 7.31 (5Η, m), 7.09 (IH, d, J 8Hz), 6.98 (IH, s), 6.77 (IH, d J 8Hz), 4.82 (2H, s), 4.63 (IH, m), 3.83 (2H, d, J 4Hz), 2.80 (2H, m), 1.52 (6H, s).
(viii) 3-(4-r(6-(Benzvir(2R)-2-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2- hydroxyethyllaminolhexyPoxylbutyl . benzenesulfonamide
A stirred mixture of 3-{4-[(6-bromohexyl)oxy]butyl}benzenesulfonamide (1 l . lg), (lR)-2- (benzylamino)-l-(2,2-dimethyl-4H-l ,3-benzodioxin-6-yl)ethanol (9g) and diisopropyl ethylamine (8.9ml) in acetonitrile (28ml) was heated at reflux for 18h. The resulting mixture was cooled to room temperature, diluted with diethyl ether (250ml) and washed with water (2x100ml) and brine (100ml) before being dried over anhydrous Na2S0 . The suspension was filtered and concentrated under reduced pressure to give the title compound (20g) as an oil. LC RT = 4.68min, δ (CDC13) 7.70 (2Η, m), 7.38 (2H, m), 7.29 (5H, m), 7.02 (IH, d, J 8.3Hz), 6.91 (IH, s), 6.73 (IH, d, J 8.3Hz), 4.79 (2H, s), 4.53 (IH, m), 3.87 (IH, m), 3.40 (5H, m), 2.69 (2H, t, J 7.2Hz), 2.54 (2H, m), 2.43 (2H, m), 1.70 (2H, m), 1.60 (2H, m), 1.51 (10H, m), 1.25 (4H, m)
(ix) 3-(4- . r6-(Benzyl .(2R)-2-hvdroxy-2-.4-hvdroxy-3- (hvdroxymethyl)phenyl .ethyl . amino)hexyl]oxy. butyl ,benzenesulfonamide
Hydrochloric acid (80ml, IM) was added dropwise to a stirred solution of 3-{4-[(6- {benzyl[(2R)-2-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide (20g) in ethanol (100ml) at 0°C. Upon complete addition the mixture was stirred at 5°C for lh before being allowed to warm to room temperature. A portion (50ml) of the ethanol was removed under reduced pressure and the remaining mixture was diluted with ethyl acetate (250ml). The mixture was then washed with water (100ml), saturated sodium bicarbonate solution (100ml) and brine (100ml) before being dried over anhydrous Na2S04. The suspension was filtered and concentrated under reduced pressure to give the title compound (16g) as an oil. LC RT = 4.02min, δ (DMSO-d6) 9.15 (1 Η, s), 7.65 (1Η, s), 7.64 (1Η, d, J 8.8Ηz), 7.45 (2H, m), 7.27 (8H, m), 6.94 (IH, dd, J 8.2Hz), 6.67
(IH, d, J 8.2Hz), 4.92 (IH, t, J 5.7Hz), 4.67 (IH, s), 4.56 (IH, m), 4.45 (2H, d, J 5.7Hz), 3.61 (2H, m), 3.34 (2H, t, J 6.3Hz), 3.28 (2H, t, J 6.2Hz), 2.66 (2H, m), 2.50 (2H, m), 2.39 (2H, m), 1.61 (2H, m), 1.50 (2H, m), 1.39 (4H, m), 1.16 (4H, m).
(x) 3-(4- ..6-( .(2R)-2-Hvdroxy-2-.4-hvdroxy-3-
(hvdroxymethyl)phenyllethvUamino)hexyl]oxy. butyl)benzenesulfonamide
5% Pd/C (8g, 50%wet) was added to a solution of 3-(4-{[6-(Benzyl{(2R)-2-hydroxy-2-[4- hydroxy-3 -(hydroxymethyl)phenyl]ethyl} amino)hexyl]oxy} butyl)benzenesulfonamide ( 16g) in IMS and the mixture was stirred under hydrogen for 6h. The resulting suspension was filtered through a plug of Celite which was then washed with IMS (160ml). The combined washings were concentrated under reduced pressure to give the title compound (12.8g) as an oil, LC RT = 3.51min, δ (CD3OD) 7.64 (IH, s), 7.61 (IH, m), 7.33 (2H, m), 7.20 (IH, s), 7.01 (I H, dd, J 2.2, 8.2Hz), 6.65 (I H, d, J 8.2Hz), 4.61 (IH, m), 4.54 (2H, s), 3.33 (4H, m), 2.72 (2H, m) 2.63 (2H, m), 2.57 (2H, m) 1.62 (2H, m), 1.46 (6H, m), 1.27 (4H, m).
Example 46
The following salts of the compound of Example 45 were prepared as described below. (i) Cinnamate Salt
Cinnamic acid (0.3g) was added to a solution of 3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide (l .Og) in methanol
(5ml) at room temperature. The solution was stirred for 5 minutes before being concentrated under reduced pressure to give a pale yellow gum. Water (10ml) was added to the gum and the reulting suspension stirred at room temperature for 24h. The suspension was then filtered to give the title compound as a white solid (0.72g), which was then recrystallised from ethanol (5ml) to give a white solid (0.54g) mp 127-128°C, δ (CD3OD) 7.73 (IH, s), 7.71 (IH, d, J 7.5Hz), 7.50 (2H, d, J 7Hz), 7.41 (3H, m), 7.32 (4H, m), 7.16 (IH, dd, J 2.2, 8.2Hz), 6.78 (IH, d, J 8.2Hz), 6.49 (IH, d, J 16.4Hz), 4.88 (IH, dd, J 3.8, 9.5Hz), 4.65 (2H, s), 3.40 (4H, m), 3.10 (2H, m) 2.99 (2H, m), 2.69 (2H, t, J 7.5Hz) 1.68 (4H, m), 1.55 (4H, m), 1.39 (4H, m).
(ii) 1 -Hydoxynaphthoate Salt
Was prepared using methods similar to those quoted above, isolation from methanol/ water gave the title compound as a white solid mp 60-69°C, δ (CD3OD) 8.28 (IH, d, J 8.2Hz), 7.85 (IH, d, J 8.8Hz), 7.72 (3H, m), 7.48 (IH, m), 7.39 (4H, m), 7.19 (IH, d, J 8.8Hz), 7.16 (IH, d, J 8.2Hz), 6.78 (IH, d, J 8.2Hz), 4.88 (IH, m), 4.65 (2H, s), 3.35 (4H, m), 3.10 (2H, m) 2.99 (2H, m), 2.66 (2H, t, J 7.5Hz) 1.65 (4H, m), 1.51 (4H, m), 1.34 (4H, m).
(iii) 4-Phenylbenzoate Salt Was prepared using methods similar to those quoted above, isolation from methanol/water gave the title compound as a white solid mp 134-136°C, δ (CD3OD) 8.01 (2H, d, J 8.1Hz), 7.73 (IH, s), 7.70 (IH, d, J 6.9Hz), 7.62 (4H, m), 7.43 (4H, m), 7.34 (2H, m), 7.16 (IH, dd, J 2.6, 8.1Hz), 6.78 (IH, d, J 8.1Hz), 4.86 (IH, m), 4.64 (2H, s), 3.42 (4H, m), 3.08 (2H, m) 2.98 (2H, t, J 7.5Hz), 2.71 (2H, t, J 7.5Hz) 1.70 (4H, m), 1.57 (4H, m), 1.40 (4H, m).
(iv) Triphenylacetate Salt
Was prepared using methods similar to those quoted above, isolation from methanol/water gave the title compound as a white solid mp 99-102°C, δ (CD3OD) 7.74 (IH, s), 7.70 (IH, d, J 6.2Hz), 7.42 (2H, m), 7.32 (IH, s), 7.27 (6H, m), 7.19 (6H, m), 7.13 (4H, m), 6.77 (IH, d, J
8.2Hz), 4.85 (I H, dd, J 4.4, 9.4Hz), 4.65 (2H, s), 3.42 (4H, m), 3.04 (2H, m) 2.94 (2H, t, J 7.5Hz), 2.72 (2H, t, J 7.5Hz) 1.70 (4H, m), 1.57 (4H, m), 1.40 (4H, m).
(v) 4-Methyl Cinnamate Salt Was prepared using methods similar to those quoted above, isolation from methanol/water gave the title compound as a white solid mp 110-113°C, δ (CD3OD) 7.73 (IH, s), 7.71 (IH, d, J 7.5Hz), 7.39 (6H, m), 7.16 (3H, m), 6.78 (IH, d, J 8.2Hz), 6.45 (IH, d, J 15.7Hz), 4.88 (IH, dd, J 3.8, lO.OHz), 4.65 (2H, s), 3.40 (4H, m), 3.10 (2H, m) 2.99 (2H, m), 2.68 (2H, t, J 7.5Hz) 2.31 (3H, s), 1.68 (4H, m), 1.55 (4H, m), 1.39 (4H, m).
(vi) 4-Methoxy Cinnamate salt
Was prepared using methods similar to those quoted above, isolation from methanol/water gave the title compound as a white solid mp 115-118°C, δ (CD3OD) 7.73 (IH, s), 7.71 (IH, d, J 6.9Hz), 7.40 (5H, m), 7.35 (IH, s), 7.16 (IH, d, J 8.2Hz), 6.89 (2H, d, J 8.8Hz) 6.78 (IH, d, J 8.8Hz), 6.37 (IH, d, J 16.4Hz), 4.88 (IH, dd, J 3.2, l O.OHz), 4.65 (2H, s), 3.78 (3H, s), 3.40 (4H, m), 3.10 (2H, m) 2.99 (2H, m), 2.68 (2H, t, J 7.5Hz) 1.68 (4H, m), 1.55 (4H, m), 1.39 (4H, m).
(vii) 3-(2-Naphthalenyl)-2-propanoate Salt
Was prepared using methods similar to those quoted above, isolation from methanol/water gave the title compound s a white solid mp 139-144°C, δ (CD3OD) 7.91 (IH, s), 7.83 (3H, m), 7.72
(3H, m), 7.59 (IH, d, J 15.7Hz), 7.47 (2H, m), 7.41 (2H, m), 7.34 (IH, s), 7.16 (IH, dd, J 2.5, 8.1Hz), 6.78 (IH, d, J 8.1Hz), 6.62 (IH, d, J 16.4Hz), 4.85 (IH, m), 4.65 (2H, s), 3.40 (4H, m), 3.08 (2H, m) 2.98 (2H, m), 2.70 (2H, t, J 7.5Hz) 1.69 (4H, m), 1.56 (4H, m), 1.39 (4H, m).
Example 47: 3-(3- { .7-( .(2R)-2-Hvdroxy-2-.4-hvdroxy-3- (hvdroxymethvDphenyllethyl}amino)heptyl1oxy>propyl)benzenesulfonamide
(i) 7-Bromoheptyl prop-2-ynyl ether
25% (w/w) aq. NaOH (700ml) was added to a stirred mixture of propargyl alcohol (70g), tetra- butyl ammonium bromide (3.5g) and 1,7-dibromoheptane (322g) maintaining the temperature below 30°C. The reaction mixture was heated at 60 °C for 5hrs then allowed to cool to room temperature and stirred overnight. Diethyl ether (350ml) and water (280ml) were added, the mixture stirred and allowed to settle. The aqueous layer was extracted with diethyl ether (210ml), the organic layers combined, dried (MgS04). The solution was concentrated to give 280g of crude material. 140g Of the crude was purified by chromatography on Biotage (800g) eluting with petroleum ether then petroleum ether : ethyl acetate (100 : 1 followed by 100 : 1.5) to give the title compound (49.6g).
NMR - 300MHz - δ (CDC13) - 4.05 (2H, d, J 2Hz), 3.45 (2H, t, J 6.5Hz), 3.35 (2H, t, J 7Hz), 2.35 (IH, s), 1.8 (2H, m), 1.5 (2H, m), 1.3 (4H, m).
(ii) 3- (3-[(7-Bromoheptyl)oxy1prop-l-vnvD benzenesulfonamide
7-Bromoheptyl prop-2-ynyl ether (55.1g) in THF (250ml) was added dropwise over ca 8h to a stirred mixture of 3-bromobenzenesulfonamide (43.5g), PdCl2(PPh3)2 (6.48g), PPh3 (1.45g), Cul (1.4g) and Et3N (52ml) in THF (250ml) at 55+ 5°C under nitrogen then the mixture heated for a further ca 15hrs. The reaction was cooled, filtered through Celite and the solids washed with THF. The solution was concentrated and the product purified by chromatography on flash silica gel (600g) eluting with petroleum etheπethyl acetate (ratios ranging successively from 19: 1 to 7:3) to give the title compound (33%) - LC RT = 5.85min.
NMR - 300MHz - δ (CDC13) - 7.95 (IH, t, J 1.5Hz), 7.78 (IH, dt, J 8, 2Hz), 7.55 (IH, dt, J 7.75, 2Hz), 7.40 (IH, t, J 8Hz), 5.0 (2H, br s), 4.3 (2H, s), 3.4 (2H, t, J 6.5Hz), 3.35 (2H, t, J 7.25Hz), 1.75 (2H, m), 1.55 (2H, m), 1.3 (4H, m).
(iii) 3- .3-r(7-Bromoheptyl)oxy1propyl)benzenesulfonamide 3-{3-[(7-Bromoheptyl)oxy]prop-l-ynyl}benzenesulfonamide (29.4g) was dissolved in Industrial Methylated Spirits (IMS) (300ml). Nuchar charcoal (15g, 50% w/w) was added and the suspension stirred at room temperature for ca 1.5h. After filtering off the charcoal and washing the filtrate with IMS (60ml) the solution was then treated in two separate lots : 5% Pd/C catalyst (11.25g, 50% wet) was added to each, the mixtures hydrogenated at atmospheric pressure and temperature for ca l-2h, the catalyst filtered off, rinsed with IMS (ca 10ml) and the filtrate concentrated to give the crude product as a solid which was recrystallised from diisopropyl ether
(100ml) to give the title compound ΆS a solid (15.1g) - LC RT = 5.91 min. NMR - 300MHz - δ (CDC13) - 7.75 (2H, m), 7.45 (2H, m), 4.9 (2H, br s), 3.42 (6H, m), 2.8 (2H, t, J 7.5Hz), 1.9 (4H, m), 1.65-1.55 (4H, m), 1.5-1.3 (4H, m). (iv) 3-(3-r(7-(Benzvir(2R)-2-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2- hydroxyethyl]amino)heptyl)oxy]propyl)benzenesulfonamide A mixture of (lR)-2-(benzylamino)-l-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)ethanol (55.8g), 3-
{3-[(7-bromoheptyl)oxy]propyl}benzenesulfonamide (63.65g), N,N-diisopropylethylamine (55ml) and acetonitrile (200ml) was stirred and heated under N2 at reflux for ca 21h. The mixture was cooled to room temperature then diethyl ether (1000ml) and water (500ml) were added and the mixture stirred. The organic phase was washed with water (500ml), then saturated brine (500ml) and dried (Na2S04). The solution was concentrated and the product purified by chromatography on flash silica gel (lOOOg), eluting with petroleum etheπethyl acetate (ratios ranging successively from 4: 1 to 1 : 1) to give the title compound (91.1%) - LC RT = 1.54min. δ (DMSO-d6) - 7.75 (2Η, m), 7.45 (IH, t, J 8Hz), 7.4 (IH, m), 7.35 (2H, s), 7.25 (5H, m), 7.05 (IH, d, J 8.5Hz), 7.0 (IH, s), 6.7 (IH, d, J 8.5Hz), 4.9 (IH, br s), 4.78 (2H, s), 4.6 (I H, m), 3.65 (IH, d, J 13.8Hz), 3.55 (IH, d, J 13.8Hz), 3.4 (IH, br s), 3.3 (4H, m), 2.1 (2H, m), 2.55 (2H, m),
2.4 (2H, m), 1.85 (2H, m), 1.45 (8H, m), 1.35 (2H, m), 1.25 (2H, m), 1.15 (4H, m).
(v) 3-(3-{r7-(BenzvU(2R)-2-hvdroxy-2-14-hvdroxy-3-
(hydroxymethyl)phenyl1ethyl}amino)heptyl]oxy)propyPbenzenesulfonamide
To a stirred,ice-cooled solution of 3-{3-[(7-{Benzyl[(2R)-2-(2,2-dimethyl-4H-l,3-benzodioxin- 6-yl)-2-hydroxyethyl]amino}heptyl)oxy]propyl}benzenesulfonamide (97.2g) in IMS (417ml) was gradually added aqueous IM hydrochloric acid (417ml) keeping the temperature below 15°C. The mixture was then stirred at room temperature for ca 5h. Saturated sodium bicarbonate (417ml) and ethyl acetate (1000ml) were then added to the mixture. The organic layer was separated off, washed with water (400ml), brine (400ml) and finally dried (Na2S04). Concentration in vacuo gave the title compound (81.9%) - LC RT = 4.01min.
δ (CDC13) - 7.75 (IH, br s), 7.70 (IH, m), 7.4-7.25 (8H, m), 7.0 (IH, d, J 8Hz), 6.95 (IH, s), 6.75 (IH, d, J 8Hz), 4.7 (2H, s), 4.55 (IH, m), 3.9 (IH, d, J 13Hz), 3.55 (IH, d, J 13Hz), 3.4 (4H, m), 2.75 (2H, t, J 7.5Hz), 2.65 (IH, m), 2.55 (2H, d, J 7Hz), 2.45 (IH, m), 1.87 (2H, m), 1.55 (4H, m), 1.3 (6H, m).
(vi) 3-(3- . r7-( ,(2R)-2-Hvdroxy-2-.4-hydroxy-3-
(hvdroxymethyl)phenyl]ethyl}amino)heptylloxy)propyl)benzenesulfonamide 3-(3-{[7-(Benzyl{(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)benzenesulfonamide (87.2g) in methanol (800ml) was hydrogenated over 5% Pd/C catalyst (28g, 50% wet) at atmospheric pressure and ambient temperature. The catalyst was removed by filtration through a Hyflo pad and the filtrate concentrated in vacuo to give the title compound (64.4g) - LC RT = 3.46min. δ (DMSO- d6) - 7.65 (2H,m), 7.45 (2H, m), 7.25 (IH, s), 6.95 (IH, dd, J 8, 2Hz), 6.67 (IH, d, J 8Hz), 5.0 (2H, br m,), 4.45 (3H, m), 3.35 (4H, m), 3.15 (2H, m), 2.1 (2H, m), 2.55-2.45 (4H, m), 1.8 (2H, m), 1.5 (2H, m), 1.35 (2H, m), 1.25 (6H, m).
Example 48:
(i) 3-(3- . r7-( .(2R)-2-Hvdroxy-2-.4-hvdroxy-3-
(hvdroxyme_hvDphenyllethyl}amino)heptyl]oxyψropyDbenzenesulfonamide (E)-3-(napthalen- 2-yl)-2-propenoate
3-(3-{[7-({(2R)-2-Hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)benzenesulfonamide
(lg) was taken up in ethanol (6ml) at room temperature with stirring and (E)-3-(napthalen-2-yl)- 2-propenoic acid (0.39g) added. The mixture was heated to ca 60°C until a solution formed. The solution was cooled to room temperature and seed crystals of the title compound added. The mixture was aged for 65h , the product filtered, washed with ethanol (1ml) and dried to give the title compound ( 1.05g) M Pt. = 135°C - 146°C
δ (MeOH - d4) 7.95 (IH, s), 7.87 (3H, m), 7.75 (3H, m), 7.60 (IH, d, J 16Hz), 7.45 (5H, m), 7.40 (IH, m), 6.8 (IH, d, J 8Hz), 6.65 (IH, d, J 16Hz), 4.9 (IH, m), 4.65 (2H, s), 3.4 (4H, m), 3.12 (2H, m), 3.05 (2H, br t, J 8Hz), 2.75 (2H, t, J 8Hz), 1.87 (2H, m), 1.72 (2H, m), 1.56 (2H, m), 1.40 (6H, m).
Alternatively:
3-(3-{[7-({(2R)-2-Hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)benzenesulfonamide (0.5g), dissolved in methanol (10ml) was treated with (E)-3-(napthalen-2-yl)-2-propenoic acid (0.194g). The clear solution was evaporated to dryness and re-dissolved in ethanol (3ml) and heated to reflux. The solution was allowed to cool to room temperature and after 48h the product filtered, washed with ethanol (2ml) and dried to give the title compound (0.58%), M Pt 135 - 146°C.
(ii) 4-Phenylbenzoate Salt
In a similar fashion to the previous example, the title salt was prepared (0.5g). The XRPD pattern of this product is shown in Figure 1. δ (MeOH - d4) 8.05 (2H, d, J 8Hz), 7.75 (2H, m), 7.65 (4H, m), 7.45 (4H, m), 7.35 (2H, m), 7.17 (IH, d, J 8Hz), 6.8 (IH, d, J 8Hz), 4.9 (s), 4.65 (2H, s), 3.42 (4H, m), 3.12 (2H, m), 3.02 (2H, m), 2.80 (2H, t, J 8Hz), 1.90 (2H, m), 1.72 (2H, m), 1.55 (2H, m), 1.40 (2H, br s).
(iii) Triphenylacetate Salt In a similar fashion, the title salt was prepared (0.485g). The XRPD pattern of this product is shown in Figure 2. δ (MeOH - d4) 7.86 (2H, m), 7.58 (2H, m), 7.48 (IH, m), 7.42 (6H, m), 7.35 (6H, m), 7.27 (4H, m), 6.92 (IH, d, J 8Hz), 5.00 (m), 4.78 (2H, s), 3.55 (4H, m), 3.50 (IH, s), 3.20 (2H, m), 3.10 (2H, m), 2.92 (2H, m), 2.05 (2H, m), 1.80 (2H, m), 1.72 (2H, m), 1.5 (6H, m).
(iv) 4-Phenylcinnamate Salt
In a similar fashion the title salt was prepared (0.243g). The XRPD pattern of this product is shown in Figure 3. δ (MeOH - d4) 1.1 (2H, m), 7.55 (6H, m), 7.35 (5H, m), 7.29 (2H, m), 7.1 (IH, d, J 8Hz), 6.75 (IH, d, J 8Hz), 6.56 (IH, d, J 15.5Hz), 4.85 (m), 4.60 (2H, s), 3.35 (4H, m), 3.05 (2H, m), 2.95 (2H, m), 2.7 (2H, t, J 8Hz), 1.8 (2H, m), 1.65 (2H, m), 1.5 (2H, m), 1.3 (6H, br s).
(v) Sulphamate Salt
In a similar fashion the title salt was prepared (0.56g). The XRPD pattern of this product is shown in Figure 4.
(vi) Sulphanilate Salt
In a similar fashion, the title salt was prepared (0.52g). The XRPD pattern of this product is shown in Figure 5. M Pt 1 17°C - 123°C δ (MeOH - d4) 7.65 (IH, s), 7.62 (IH, d, J 7Hz), 7.45 (2H, m), 7.35 (2H, m), 7.25 (IH, s), 7.05 (IH, d, J 7Hz), 6.7 (IH, d, J 8Hz), 6.55 (2H, d, J 8Hz), 4.9 (m), 4.55 (2H, s), 3.33 (4H, m), 3.05
(2H, m), 2.95 (2H, t, J 8Hz), 2.65 (2H, t, J 8Hz), 1.8 (2H, m), 1.6 (2H, m), 1.48 (2H, m), 1.3 (6H, br s)
Example 49: N2-(r3-(4-(r6-(((2R)-2-Hvdroxy-2-r4-hvdroxy-3-
(hvdroxymethvPphenyl1ethvUamino)hexyl]oxy)butyl)phenyl1sulfonyU glycinamide acetate i) N2- (3-Iodophenyl)sulfonyl]-N2-{ 2-(trimethylsilyl)ethoxy1methyU glycinamide N2-[(3-Iodophenyl)sulfonyl]glycinamide (0.14g) was stirred with sodium hydride (60% oil dispersion, 0.02g) in DMF (2ml) at 21° under nitrogen for 15min. 2-Trimethylsilylethoxymethyl chloride (0.08ml) was added and stirring was continued for 1.5h. The mixture was poured into pH 6.4 phosphate buffer and the product was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (MgS04), concentrated and applied to a silica Bond Elut Cartridge (5g) in dichloromethane containing methanol. The cartridge was eluted with dichloromethane, diethyl ether and ethyl acetate to give the title compound (0.16g), LCMS RT = 3.49min.
ii) Ν2- (3-(4-r(6-Iodohexyl)oxylbut-l-vnvUphenyl)sulfonyll-Ν2-(r2-
(trimethylsilyl)ethoxy]methyl . glycinamide compound with N2- (3-{4- (6-bromohexyl)oxy]but- l-ynyl}phenyDsulfonyl1-N2-{r2-(trimethylsilyDethoxy1methyl}glycinamide (55:45) N2-[(3-Iodophenyl)sulfonyl]-N2-{[2-(trimethylsilyl)ethoxy]methyl}glycinamide (0.16g) was stirred with 6-bromohexyl but-3-ynyl ether (0.086g) in acetonitrile (2ml) and diisopropylethylamine (2ml) under nitrogen for 10 min. Cuprous iodide (0.0 lg) and dichlorobis(triphenylphosphine)palladium (0.02g) were added and the stirring continued for 2h. The solution was evaporated to dryness and applied to a Bond Elut cartridge (5g) in dichloromethane. The cartridge was eluted with dichloromethane and diethyl ether to give the title compounds (0.165g), LCMS RT 3.93min (bromide) and 4.02min (iodide).
ii) 2-Azido-l-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)ethanone
2-Bromo-l-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)ethanone (Glaxo DE 3513885, 1985) (52g) in DMF (300ml) was treated with sodium azide (12.24g) and the mixture was stirred for 2h at 20°C. The reaction mixture was diluted with ethyl acetate and washed with water and dried (MgS04). The solvent was removed under reduced pressure to give the title compound (39 Λ I %). TSP+ve 248(MH)+.
iii) (lR)-2-Azido-l-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)ethanol
R-(+)-2-Methyl-CBS-oxazaborolidine solution in toluene (IM, 7.5ml) was added to THF (75ml) and the solution was diluted to 0°C. Borane-THF complex (IM solution in THF, 125ml) was added and the mixture was stirred under nitrogen for 15min. A solution of 2-azido-l-(2,2- dimethyl-4H-l ,3-benzodioxin-6-yl)ethanone (24.7g) in THF (250ml) was added dropwise over 1.5h at 5°C. The mixture was stirred for a further lh and then cautiously treated with 2M HCI (100ml). The reaction mixture was extracted with ether and the organic layer was washed with 2M HCI, NaHC03, brine, dried (MgS04). The solvent was removed by evaporation and the residue was chromatographed on a Biotage column eluting with diethyl ether-petrol (40-60°C)
(1 :9; 1 : 1) to give the title compound (\6.99%). ES+ve 250 (MH)+.
iv) (lR)-2-Amino-l-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)ethanol (lR)-2-Azido-l-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)ethanol (16.99g) was hydrogenated over 10% Pd-C (lg) in ethanol (300ml). The catalyst was collected by filtration, and washed with ethanol. The combined washings were evaporated under reduced pressure and the residue was triturated in diethyl ether to give the title compound (5.86%). The mother liquors were chromatographed on a Biotage column eluting with toluene:ethanol:aqueous ammonia (85:14: 1) to give a further batch of the title compound (5.99%). LCMS RT=1.68 min, ES+ve 206 (MH- H20)+.
vi) N2-, (3- (4-. (6- . r(2R)-2-(2.2-Dimethyl-4H- 1.3 -benzodioxin-6-yl)-2- hvdroxyethyl1amino)hexyl)oxy]but-l-vnyl . phenyl)sulfonyl1-N2-{r2-
(trimethylsilyl)ethoxylmethyU glycinamide (lR)-2-Amino-l-(2,2-dimethyl-4H-l,3-benzodioxin-6-yl)ethanol (0.134g) was stirred with N2-
[(3-{4-[(6-iodohexyl)oxy]but-l-ynyl}phenyl)sulfonyl]-N2"{[2-
(trimethylsilyl)ethoxy]methyl}glycinamide compound with N2"[(3-{4-[(6-bromohexyl)oxy]but- l-ynyl}phenyl)sulfonyl]-N2-{[2-(trimethylsilyl)ethoxy]methyl}glycinamide (55:45) (0.165g) in
DMF (3ml) for 4 days at 21°. The mixture was evaporated to dryness and applied to a silica Bond Elut Cartridge (5g) in ethyl acetate. This was eluted with ethyl acetate and then 10% methanol in ethyl acetate to give the title compound (0.08 lg) LCMS RT = 3.04min. vii) N2-r(3-{4-r(6-(r(2R)-2-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-2- hvdroxyethyl]aminolhexyl)oxy]butvUphenyl)sulfonyl]-N2-{r2- (trimethylsilyl)ethoxyl methyl , glycinamide
N2-[(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-l,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]but-l-ynyl}phenyl)sulfonyl]-N2-{[2-
(trimethylsilyl)ethoxy]methyl}glycinamide (0.09g) was stirred with platinum oxide (0.023g) in ethanol (20ml) under hydrogen for 3.5h. The catalyst was filtered off with the aid of celite and the filter cake was leached with ethanol. The combined filtrates were evaporated to give the title compound (0.091 g) LCMS RT = 3.10min.
viii) N2- ..3-(4- . r6-( ,(2R)-2-Hvdroxy-2-f4-hvdroxy-3-
(hydroxymethvDphenyl . ethyl) amino)hexyl]oxy}butyl)phenyl]sulfonvU glycinamide acetate
N2-[(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-l ,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)sulfonyl]-N2-{[2- (trimethylsilyl)ethoxy]methyl}glycinamide (0.091g) was stirred under a reflux condenser at 80° in acetic acid (2ml) and water (1ml) for 3.5h. The solution was evaporated to dryness and re- evaporated twice with methanol to give a gum. The residue was dissolved in methanol and loaded onto two 20 x 20cm preparative silica gel coated plates (1mm layer). The plates were run in dichloromethane:ethanol:0.880 ammonia solution, 25:8: 1 and elution of the main band and evaporation gave a gum. This was dissolved in acetic acid (2ml) and evaporated to dryness and re-evaporated with methanol to give the title compound (0.019g) LCMS RT = 2.31 min, ES+ve 552 (MH)+.
Example 50: 6α. 9α-Difluoro-17α-[(2-furanylcarbonvDoxy]-l lβ-hvdroxy-16α-methyl-3-oxo- androsta-l,4-diene-17β-carbothioic acid S-fluoromethyl ester Unsolvated Form 1
(a) 6α. 9α-Difluoro-17α-[(2-furanylcarbonyl)oxy]-l l β-hydroxy-16α-methyl-3-oxo-androsta-l. 4-diene-17β-carbothioic acid
A solution of 6α, 9α-difluoro-l l β, 17α-dihydroxy-16α-methyl-3-oxo-androsta-l,4-diene-17β- carbothioic acid (prepared in accordance with the procedure described in GB 2088877B) (18g, 43.64mmol) in anhydrous dichloromethane (200ml) and triethylamine (15.94ml, 1 14mmol) was treated at <5 °C with a solution of 2-furoyl chloride (11.24ml, 1 14mmol) in anhydrous dichloromethane (100ml) over approximately 40min. The solution was stirred at <5 °C for 30min. The resulting solid was collected by filtration, washed successively with 3.5% aqueous sodium hydrogen carbonate solution, water, IM hydrochloric acid, and water and dried in vacuo at 60 °C to give a cream coloured solid. The dichloromethane filtrate was washed successively with 3.5% sodium hydrogen carbonate solution, water, IM hydrochloric acid, water, dried (Na2S04) and evaporated to give a cream coloured solid which was combined with that isolated above. The combined solids (26.9g) were suspended in acetone (450ml) and stirred. Diethylamine (16.8ml, 162mmol) was added and the mixture stirred at room temperature for 4.5h. The mixture was concentrated and the precipitate collected by filtration and washed with a little acetone. The washings and filtrate were combined, concentrated and loaded onto a silica gel Biotage column which was eluted with 24: 1 chloroform: methanol. Fractions which contained the more polar component were combined and evaporated to give a cream coloured solid. This was combined with the solid isolated above and dried in vacuo to give a pale beige coloured solid (19.7g). This was dissolved in warm water, the pH adjusted to 2 with concentrated hydrochloric acid and the mixture extracted with ethyl acetate. The organic extract was dried (Na2S04) and evaporated to give, after drying at 50°C, the title compound as a cream coloured solid (18.081g, 82%): LCMS retention time 3.88min, m/z 507 MIT\ NMR δ (CDC13) includes
7.61 (IH, m), 7.18 - 7.12 (2H, m), 6.52 (IH, dd, J 4, 2Hz), 6.46 (IH, s), 6.41 (IH, dd, J 10, 2Hz), 5.47 and 5.35 (IH, 2m), 4.47 (IH, bd, J 9Hz), 3.37 (IH, m), 1.55 (3H, s), 1.21 (3H, s), 1.06 (3H, d, J7Hz).
A suspension of the product of part (a) (2.5g, 4.94mmol) was dissolved in anhydrous N, N- dimethylformamide (25ml) and sodium hydrogen carbonate (465mg, 5.53mmol) was added. The mixture was stirred at -20°C and bromofluoromethane (0.77ml, 6.37mmol) was added and the mixture was stirred at -20°C for 2h. Diethylamine (2.57ml, 24.7mmole) was added and the mixture stirred at -20°C for 30min. The mixture was added to 2M hydrochloric acid (93ml) and stirred for 30min. Water (300ml) was added and the precipitate was collected by filtration, washed with water and dried in vacuo at 50°C to give a white solid which was recrystallised from acetone/water (to yield the acetone solvate of 6α, 9α-difluoro-17α-[(2-furanylcarbonyl)oxy]- 1 lβ-hydroxy-16α-methyl-3-oxo-androsta-l,4-diene-17β-carbothioic acid S-fluoromethyl ester) and dried in vacuo at 50°C to give the title compound (2.35 lg, 88%): LCMS retention time 3.66min, m/z 539 MIT", NMR δ (CDC13) includes 7.60 (IH, m), 7.18 - 7.11 (2H, m), 6.52 (IH, dd, J4.2Hz), 6.46 (IH, s), 6.41 (IH, dd, J 10, 2Hz), 5.95 and 5.82 (2H dd, J 51 , 9Hz), 5.48 and 5.35 (IH, 2m), 4.48 (IH, m), 3.48 (IH, m), 1.55 (3H, s), 1.16 (3H, s), 1.06 (3H, d, J7Hz).
Example 51 : 6α.9α-Difluoro-l l β-hvdroxy-16α-methyl-17α-[(4-methyl-l,3-thiazole-5- carbonyl)oxy1-3-oxo-androsta-l,4-diene-17β-carbothioic acid S-fluoromethyl ester
Example 51 was prepared using a method analogous to that described for Example 50: LCMS retention time 3.51min, m/z 570 MH+
BIOLOGICAL ACTIVITY The potencies of the aforementioned compounds were determined using frog melanophores transfected with the human beta 2 adrenoreceptor. The cells were incubated with melatonin to induce pigment aggregation. Pigment dispersal was induced by compounds acting on the human beta 2 adrenoreceptor. The beta 2 agonist activity of test compounds was assessed by their ability to induce a change in light transmittance across a melanophore monolayer (a consequence of pigment dispersal). At the human beta 2 adrenoreceptor, compounds of examples 1- 49 had IC50 values below 1 μM.
Potency at other beta adrenoreceptor subtypes was determined using Chinese hamster ovary cells transfected with either the human beta 1 adrenoreceptor or the human beta 3 adrenoreceptor. Agonist activity was assessed by measuring changes in intracellular cyclic AMP.
The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims:

Claims

Claims
A compound of formula (I):
Figure imgf000077_0001
or a salt, solvate, or physiologically functional derivative thereof, wherein:
m is an integer of from 2 to 8; n is an integer of from 3 to 1 1; with the proviso that m + n is 5 to 19;
R1 is -XS02NR6R7
wherein X is -(CH2)P- or C2.6 alkenylene;
R6 and R7 are independently selected from hydrogen, C].6alkyl,
C3.7cycloalkyl, C(0)NR8R9, phenyl, and phenyl (d.4alkyl)-, or R6 and R7, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7- membered nitrogen containing ring, and R6 and R7 are each optionally substituted by one or two groups selected from halo,
C,.6alkyl, Cι.6haloalkyl, C,.6alkoxy, hydroxy-substituted Cι.6alkoxy, -C02R8, -S02NR8R9,
-CONR8R9, -NR8C(0)R9, or a 5-, 6- or 7-membered heterocylic ring;
R8 and R9are independently selected from hydrogen, C^alkyl,
C3.6cycloalkyl, phenyl, and phenyl (Cι.4alkyl)-; and p is an integer of from 0 to 6;
R2 and R3 are independently selected from hydrogen,
Figure imgf000077_0002
halo, phenyl, and Ci-βhaloalkyl; and
R4 and R5 are independently selected from hydrogen and Cι.4alkyl with the proviso that the total number of carbon atoms in R4 and R5 is not more than 4.
2. A compound of formula (la):
Figure imgf000077_0003
or a salt, solvate, or physiologically functional derivative thereof, wherein R1 is as defined in claim 1 for formula (I).
3. A compound of formula (lb):
Figure imgf000078_0001
or a salt, solvate, or physiologically functional derivative thereof, wherein R1 is as defined in claim 1 for formula (I).
4. A compound according to claim 1 or claim 2 selected from:
3 -(4- { [6-( {(2R)-2-Hydroxy-2- [4-hydroxy-3 -(hydroxymethyl)phenyl]ethyl } - amino)hexyl]oxy}butyl)benzenesulfonamide; 3 -(4- { [6-( {(2S)-2-Hydroxy-2- [4-hydroxy-3 -(hydroxymethyl)phenyl]ethyl } - amino)hexyl]oxy}butyl)benzenesulfonamide; 3-(4-{[6-({(2R S)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)hexyl]oxy}butyl)benzenesulfonamide; and salts, solvates, and physiologically functional derivatives thereof.
A compound according to claim 1 or claim 3 selected from:
3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)heptyl]oxy}propyl)benzenesulfonamide; 3-(3-{[7-({(2S)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)heptyl]oxy}propyl)benzenesulfonamide; 3-(3-{[7-({(2R/S)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}- amino)heptyl]oxy}propyl)benzenesulfonamide; and salts, solvates, and physiologically functional derivatives thereof.
6. A compound according to any of claims 1 to 5 wherein the compound is in the form of a salt formed with a pharmaceutically acceptable acid selected from cinnamic, substituted cinnamic, triphenylacetic, sulphamic, sulphanilic, naphthaleneacrylic, benzoic, 4-methoxybenzoic, 2- or 4- hydroxybenzoic, 4-chlorobenzoic and 4-phenylbenzoic acid. A method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which a selective β2-adrenoreceptor agonist is indicated, which comprises administration of a therapeutically effective amount of a compound of formula (I), (la) or (lb) according to any of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
8. A compound of formula (I), (la) or (lb) according to any of claims 1 to 5 or a pharmaceutically 10 acceptable salt, solvate, or physiologically functional derivative thereof for use in medical therapy.
9. A pharmaceutical formulation comprising a compound of formula (I), (la) or (lb) according to any of claims 1 to 5 or a pharmaceutically acceptable salt, solvate, or physiologically functional
15 derivative thereof, and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients.
10. A combination comprising a compound of formula (I), (la) or (lb) according to any of claims 1 to 5 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof,
20 and one or more other therapeutic ingredients.
1 1. A combination according to claim 10 wherein the other therapeutic ingredient is a PDE4 inhibitor or an anticholinergic or a corticosteroid.
25 12. A combination comprising a compound of formula (I), (la) or (lb) according to any of claims 1 to 5 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and 6α,9α-difluoro- 17α- [(2-furanylcarbonyl)oxy]- 11 β-hydroxy- 16α-methyl-3 -oxo-androsta- 1 ,4- diene-17β-carbothioic acid S-fluoromethyl ester.
30 13. The use of a compound of formula according to any of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which a selective β2- adrenoreceptor agonist is indicated.
35 14. A process for the preparation of a compound of formula (I), (la) or (lb) according to any of claims 1 to 5 or a salt, solvate, or physiologically functional derivative thereof, which comprises: (a) deprotection of a protected intermediate, for example of formula (II):
Figure imgf000080_0001
or a salt or solvate thereof, wherein R1, R2, R3, R4, R5, m, and n are as defined for the compound of formula (I), (la) or (lb), and R8, R9, and R10 are each independently either hydrogen or a protecting group provided that at least one of R8, R9, and R10 is a protecting group;
(b) alkylation of an amine of formula (XII)
Figure imgf000080_0002
wherein R8 and R9 and R1 are each independently either hydrogen or a protecting group, with a compound of formula (XIII):
L2CR4R5(CH2)m
Figure imgf000080_0003
wherein R1, R2, R3, R4, R5, m, and n are as defined for the compound of formula (I) or (la) and L2 is a leaving group;
(c) reacting a compound of formula (XVII):
Figure imgf000080_0004
wherein R8, R9 and R14 are as hereinbefore defined and L4 is a leaving group, with an amine of formula (XVIII): ,10. ,,. ,^r-.4-,5
R "HNCR'R-(CH2)m— O — (CH2)n k ' . (XVIII)
wherein R to R , R , m and n are as hereinbefore defined; or
(d) removal of a chiral auxiliary from a compound of formula (Ila):
Figure imgf000081_0001
(Ila)
wherein R1 - R5, R8, R9, m and n are as hereinbefore defined and R15 represents a chiral auxiliary;
followed by the following steps in any order:
(i) optional removal of any protecting groups; (ii) optional separation of an enantiomer from a mixture of enantiomers;
(iii) optional conversion of the product to a corresponding salt, solvate, or physiologically functional derivative thereof.
A novel intermediate selected from those of formulae (II) (III) and (IV).
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